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Category Archives: Mesenchymal Stem Cells

Osteoarthritis Treatment – Stem Cell Therapy In India

Posted: July 24, 2016 at 10:44 pm

What is Osteoarthritis?

Osteoarthritis (OA) is a degenerative joint disorder. It is a common type of arthritis where nearly 15 million patients are affected by this condition every year in India. The main reason for OA is wear and tear of the articular cartilage and ligament, loss of synovial fluid or loss of regenerative capacity of chondrocytes. The articular cartilage is especially vulnerable to damage. Normal load-bearing capacity and biomechanical properties of thinning cartilage are severely compromised during the course of disease progression. Common joints that are affected by Osteoarthritis are Knee, Hip, Hand Joints, Neck etc.

What Causes Osteoarthritis?

Osteoarthritis symptoms and signs

Osteoarthritis is a progressive joint disease, The most common symptoms of osteoarthritis are:

Common symptoms related to the following conditions possibly treated by mesenchymal stem cells for osteoarthritis as well as bone-related injuries:

Osteoarthritis is characterized by joint pain, stiffness, inflammation and reduced movement of the joints.

OA being a degenerative disease and with pain making day to day activities more difficult, It is crucial to find a way to cope with the pain and the discomfort. There are several exercises for osteoarthritis of the knee.

Although surgical and pharmaceutical interventions are currently available for treating OA, restoration of normal cartilage function has been difficult to achieve.

The fundamental question that comes to mind:

With science evolving, versatile options are being made available to treat such conditions. Unistem have treated number of severe osteoarthritis cases in india through alternative medical treatments. These include usage of Platelet Rich Plasma (PRP) derived from ones own blood, Mesenchymal stem cells etc., For more details click here.

The procedure of using PRP and MSCs is simple. It hardly takes a few minutes to complete and the patient can return home the very same day.

The benefits that have been observed are reduction in pain, reduced progression of the condition, and an overall improvement in the quality of life.

**Use of Stem cells is in evolution phase and categorized non-conventional**

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Osteoarthritis Treatment – Stem Cell Therapy In India

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MesenCult Mesenchymal Stem Cell Stimulatory Supplements Human

Posted: at 10:43 pm

Abstract

Cell transplantation has been well explored for cartilage regeneration. We recently showed that the entire articular surface of a synovial joint can regenerate by endogenous cell homing and without cell transplantation. However, the sources of endogenous cells that regenerate articular cartilage remain elusive. Here, we studied whether cytokines not only chemotactically recruit adipose stem cells (ASCs), mesenchymal stem cells (MSCs), and synovium stem cells (SSCs) but also induce chondrogenesis of the recruited cells. Recombinant human transforming growth factor-3 (TGF-3; 100 ng) and/or recombinant human stromal derived factor-1 (SDF-1; 100 ng) was control released into an acellular collagen sponge cube with underlying ASCs, MSCs, or SSCs in monolayer culture. Although all cell types randomly migrated into the acellular collagen sponge cube, TGF-3 and/or SDF-1 recruited significantly more cells than the cytokine-free control group. In 6 wk, TGF-3 alone recruited substantial numbers of ASCs (55865) and MSCs (30252), whereas codelivery of TGF-3 and SDF-1 was particularly chemotactic to SSCs (400120). Proliferation of the recruited cells accounted for some, but far from all, of the observed cellularity. TGF-3 and SDF-1 codelivery induced significantly higher aggrecan gene expression than the cytokine-free group for ASCs, MSCs, and SSCs. Type II collagen gene expression was also significantly higher for ASCs and SSCs by SDF-1 and TGF-3 codelivery. Remarkably, the expression of aggrecan and type II collagen was detected among all cell types. Thus, homing of multiple stem/progenitor cell populations may potentially serve as an alternative or adjunctive approach to cell transplantation for cartilage regeneration.

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Mesenchymal Stem Cell Based Therapy for the Treatment of …

Posted: July 23, 2016 at 8:44 pm

Verified March 2015 by Hospital de Cruces

Sponsor:

Collaborators:

Hospital Universitario Getafe

Hospital Infantil Universitario Nio Jess, Madrid, Spain

Information provided by (Responsible Party):

Clara I. Rodrguez, Hospital de Cruces

ClinicalTrials.gov Identifier:

NCT02172885

First received: June 12, 2014

Last updated: March 17, 2015

Last verified: March 2015

The purpose of this study is to determine the safety and effectiveness of two infusions of characterized HLA-identical MSC in non immunosuppressed children with Osteogenesis Imperfecta (OI).

Two Mesenchymal Stem Cell infusions

Mesenchymal Stem Cell Infusions

The principal aim of this trial is to assess the safety of non-mutated HLA-identical Mesenchymal stem cell (MSC) transplantation for OI pediatric patients irrespective of treatment with biphosphonates. Since MSC are inherently non-immunogenic and do not elicit proliferation of allogeneic lymphocytes (in co-culture experiments), a cell therapy based on HLA-identical or histocompatible (at least 5 shared out of 6 HLA antigens) allogenic MSC may be accomplished without subjecting the patients to immunosuppressor treatment. Adverse secondary effects due to immunosuppressor treatment will be avoided using this strategy thus patients may benefit from two cellular infusions. The patients will be followed for 3 and a half years post their second and last MSC infusion.

Inclusion Criteria:

Exclusion Criteria:

Please refer to this study by its ClinicalTrials.gov identifier: NCT02172885

Hospital de Cruces

Hospital Universitario Getafe

Hospital Infantil Universitario Nio Jess, Madrid, Spain

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Stem cell treatment for patients with autoimmune disease …

Posted: July 22, 2016 at 7:43 am

Prolonged life expectancy, life style and environmental changes have caused a changing disease pattern in developed countries towards an increase of degenerative and autoimmune diseases. Stem cells have become a promising tool for their treatment by promoting tissue repair and protection from immune-attack associated damage. Patient-derived autologous stem cells present a safe option for this treatment since these will not induce immune rejection and thus multiple treatments are possible without any risk for allogenic sensitization, which may arise from allogenic stem cell transplantations. Here we report the outcome of treatments with culture expanded human adipose-derived mesenchymal stem cells (hAdMSCs) of 10 patients with autoimmune associated tissue damage and exhausted therapeutic options, including autoimmune hearing loss, multiple sclerosis, polymyotitis, atopic dermatitis and rheumatoid arthritis. For treatment, we developed a standardized culture-expansion protocol for hAdMSCs from minimal amounts of fat tissue, providing sufficient number of cells for repetitive injections. High expansion efficiencies were routinely achieved from autoimmune patients and from elderly donors without measurable loss in safety profile, genetic stability, vitality and differentiation potency, migration and homing characteristics. Although the conclusions that can be drawn from the compassionate use treatments in terms of therapeutic efficacy are only preliminary, the data provide convincing evidence for safety and therapeutic properties of systemically administered AdMSC in human patients with no other treatment options. The authors believe that ex-vivo-expanded autologous AdMSCs provide a promising alternative for treating autoimmune diseases. Further clinical studies are needed that take into account the results obtained from case studies as those presented here.

In the 21st century, live expectancy has rapidly progressed as has the number of previously uncommon diseases with no treatment. Stem cell based therapies are suggested to be able to repair and regenerate tissues in diseases associated with age, changed life style and environmental exposure, such as autoimmune disease and stroke. In particular, mesenchymal stem cells (MSCs) have been applied to treat these diseases [13]. However, the lack of optimized culture protocols for achieving sufficient number of cells, safety issues concerning ex-vivo-expanded cells, the possible reduction in potency of stem cells derived from aged people and patients with autoimmune disease has put into question clinical applications of autologous stem cells in these patients.

In order to apply human autologous adipose tissue derived MSC (hAdMSC) in the clinical setting, we developed a standardized protocol to isolate and culture-expand AdMSC from minimal amounts of fat in vitro, achieving sufficient cell numbers for multiple therapeutic inventions [4]. Expanded AdMSCs maintained the potency for effective differentiation independently of donor age and disease status [5]. The confirmed genetic stability and in vivo safety of ex-vivo-expanded hAdMSCs in animal models and patients [4] indicate that AdMSCs from older persons are applicable for autologous therapy and are comparable to those derived from young donors [5]. Furthermore, we investigated the migration ability of hAdMSCs and their in vivo homing in animal model after systemic infusion.

MSC include a number of stem cells with an inherent ability for self-renewal and differentiation potential for mesodermal and other embryonic lineages, including adipocytes, osteocytes, chondrocytes, hepatocytes, neurons, muscle cells and epithelial cells [68], depending on the surrounding microenvironment. A large body of evidence demonstrated that MSC commonly have immunomodulatory and anti-inflammatory properties [912]. While the differentiation properties of MSC seem to dependent on microenvironmental clues in vivo, the immunomodulatory effects appear to be rather intrinsic and thus present an attractive basis for the therapy of autoimmune and inflammatory diseases by systemic infusion. Moreover, intrinsic properties of MSC demonstrated secretion of various factors, modulation of the local environment and activation of endogenous progenitor cells [13, 14]. Hence, MSC therapy evoked therapeutic promises for graft-versus-host disease (GVHD), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), diabetes, myocardial infarction, thyroditis and different types of neurological disorders, among others [1523].

Various routes of administration of MSCs, including intravenous (i.v.) [24], intraarterial [25] or intracerebral [26] were reported for stem cell application. Of these routes, i.v. is a convenient strategy to deliver cells and therapeutic effects to the injury site. Intravenously injected MSC may be transiently trapped in the lungs, sequestered in the spleen, and are predominantly eliminated by kidneys [27]. Initial accumulation of MSC in the lungs may induce secretion of secondary anti inflammatory effectors [28].The recent demonstration of in vivo homing properties of bone marrow derived MSCs and AdMSCs has further stimulated i.v. application of MSC for therapy [29]. In this review, we describe several cases of autologous AdMSCs application in autoimmune conditions, including autoimmune hearing loss, MS, polymyotitis (PM), atopic dermatitis (AD) and RA. We suggest that multiple infusions of AdMSC may establish immune homeostasis over long periods of time.

Minimal criteria have been proposed to define MSCs by the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy. These are: 1) plastic adherence ability; 2) lack of hematopoietic markers, such as CD45, CD34, CD14, CD11b, CD79, CD 19, or HLA-DR; 3) tripotential mesodermal differentiation potency into osteoblasts, chondrocytes, and adipocytes; and 4) immunomodulatory capability [30]. In addition to their mesodermal differentiation capability, MSCs were also shown to differentiate in vitro into the ectodermal lineage such as neurons, but also into the endodermal lineage such as myocytes and hepatocytes [7, 31]. The conditions for differentiation of engrafted MSCs in vivo might be more complex and regulated by microenvironmental cluses of local tissues. For example, MSCs engrafted into heart could differentiate into cardiomyocytes, smooth muscle cells, and vascular endothelial cells [3234]. In addition, through a series of signals from local tissue, engrafted MSCs can be induced to secrete diverse cytokines that posses trophic and immunomodulatory functions and subsequently contribute to tissue repair and regeneration [11].

MSC were first isolated as fibroblast colony-forming units (CFU-Fs) or marrow stromal cells from bone marrow (BMMSC) by Friedenstein and colleagues [35]. Their most common name is based on their property of differentiate into a variety of mesodermal tissues including bone, cartilage and fat. MSCs were found in various organs and tissues, including fat, periosteum, synovial membrane, synovial fluid, muscle, dermis, deciduous teeth, pericytes, trabecular bone, infrapatellar fat pad, articular cartilage, umbilical cord and cord blood [36, 37], and placenta [38].

BMMSCs have first been applied for therapy [39, 40]. However, aspirating BM from the patient is an invasive procedure that yields only low numbers of cells (about 1-10 per 1 105 or 0.0001-0.01% of all BM nucleated cells), requiring high expansion rates [41]. Furthermore, the therapeutic potential of BMMSCs may be diminished with increasing donor age and is associated with declining
differentiation capacity and reduced vitality in vitro [42]. In any case, for autologous transplantation, expanded BMMSCs and AdMSCs have safely been applied in numerous human studies [4, 39, 40].

Adipose tissue is an attractive source of MSCs for autologous stem cell therapy, because adipose tissue is easily obtainable in sufficient quantities using a minimally invasive procedure [23, 43]. In addition, adipose tissues contain more MSCs than BM (about 100, 000 MSCs per gram of fat) [44]. Moreover, differentiation and immunomodulatory potencies of AdMSCs are equivalent to those of BMMSCs [23].

The efficacy of AdMSCs in treating various diseases has been reported in vivo [45]. Local or systemic administration of AdMSCs was reported to have repair capacity in myocardial infarction [19] liver injury [24], hypoxia-ischemia-induced brain damage [46], allergic rhinitis [47] and muscular dystrophy [48]. Furthermore, AdMSCs are immune regulatory and potentially suitable to treat immune-related diseases including GVHD [15], MS [16], rheumatic disease [17, 18] and thyroditis [20].

Due to the small number of MSC in tissues, ex vivo expansion is required to generate the cell quantities required to achieve therapeutic results with MSCs through systemic delivery. In case of BMMSCs, however, long-term culture alters the quality of MSCs, including morphological changes, attenuated expression of specific surface markers, reduced proliferative capacity, differentiation potential [4952], and trophic activity [53].

To produce sufficient numbers of hAdMSCs for stem cell therapy, optimized culture conditions were developed [4], which allow proliferation of hAdMSC from minimal amounts of fat since large amounts of fat are rarely obtainable from patients suffering from incurable diseases. Usage of a special cannular maximizes survival rate of stem cells in fat tissues and a 3 times higher rate of subsequent early stem cell attachment when compared to other devices. The developed cell collection, cultivation and expansion protocol requires less than 5 g fat to obtain more than 109 cells (after 3 passages). To improve proliferation and differentiation of AdMSC, we tested more than 15 commercially available culture media and eventually developed the hAdMSC culture media, named as RCME (MSC attachment media) and RKCM (MSC proliferation media) [4]. These media provide high viability, shortened doubling times and maintained morphology and improved potency.

The characteristics, stability, toxicity, and tumorigenicity of the culture-expanded hAdMSCs were determined in animals and in human studies [4]. With regard to the safety of culture-expanded stem cells in vitro, genetically stability and consistency on the morphological, immunophenotypic, and differentiation characteristics, as well as toxicity and tumorigenicity need to be verified. We demonstrated that cultured hAdMSCs showed the typical immunophenotype and differentiation capability of MSCs [4]; cells expressed MSC markers CD90, CD105, CD44 and CD29, but did not express hematopoietic or endothelial markers (CD31, CD34 and CD45) and differentiated to adipogenic, osteogenic, neurogenic, myogeneic and chondrogeneic lineages in vitro. Culture-expanded hAdMSCs were genetically stable for at least 12 passages as determined by karyotype and single nucleotide polymorphism (SNP) assays.

Cells suspended in physiological saline maintained their MSC properties, viability and potency at cold storage conditions (2 to 8C) for at least 72 h, a critical time period for shipping stem cells into the clinic. However, we noticed that physical vibration during shipment might negatively impact cell viability. No evidence of bacterial, fungal, or mycoplasma contamination was observed in cells tested before shipping and cell viability evaluated by trypan blue exclusion was > 95% prior to cell transplantation.

To test the toxicity of hAdMSCs, different cell doses were intravenously injected into immunodeficient severe combined immunodeficiency (SCID) mice, and mice were observed for 13 weeks. Even at the highest cell dose (2.5 108 cells/kg body weight), mice showed no sign of discomfort. Although the safety of i.v. injection of culture expanded autologous and allogenic MSCs has been confirmed in patients [54] in numerous human clinical studies including osteogenesis imperfect [55], metachromatic leukodystrophy [56], acute myocardial infarction [57] and GVHD [58], there were some reports presenting that MSCs can induce sarcoma [59] or facilitate the growth of tumors [60]. In order to test tumorigenicity of hAdMSCs, we performed a tumorigenicity test in Balb/c-nude mice for 26 weeks. Even at the highest cell dose (2 108 MSCs/kg, subcutaneous injection), no evidence of tumor development was found. The safety of hAdMSCs was further investigated in a phase I human clinical trial, with no serious adverse event after i.v. administration of 4 108 hAdMSCs within an observation period of 12 weeks [4]. The minor adverse events found are common to spinal cord injury patients and disappeared spontaneously or were alleviated with medication. One idiopathic case of asymptomatic hyperthyroidism that did not require medical treatment remained sustained during follow-up. Based on these studies, we conclude that the systemic administration of hAdMSCs is safe and does not induce tumor development. In line with these data, Vilalta et al. [61] reported that hAdMSCs implanted in mice tended to maintain a steady state, and no detectable chromosomal abnormalities or tumors formed during the 8 months of residence in the host’s tissues. Notably, the development of sarcoma in the study of Tolar et al was due to cytogenetically abnormal culture-expanded MSCs [59]. In addition, Izadpanah et al. [62] demonstrated that long-term cultivation of MSC beyond passage 20 may result in their transformation to malignant cells. These results indicate that it is essential to control genetic stability of culture-expanded cells.

Because many diseases that are candidates for stem cells therapy are age-associated degenerative diseases, stem cells obtained from the elderly for autologous use should possess potency in order to have therapeutic effects. In terms of BMMSCs, there have been controversial results regarding the effects of aging. Using human BMMSCs from juveniles and adults seeded onto three-dimensional scaffolds, Mendes et al. [63] have demonstrated that actual bone formation decreased significantly as patient age increased. Huibregtse et al. [64] demonstrated that overall reduction in colony-forming efficiency was observed in rabbit BMMSCs derived from older animals. Bergman et al. [65] demonstrated that differences in basal proliferation rates were observed between young and old BMMSCs isolated from mice, while production of early markers of osteoblastic differentiation in vitro were equivalent. Stenderup et al. [42] have shown that human BMMSC isolated from older donors have a decreased lifespan and rate of population doubling, while both BMMSCs formed similar amounts of bone both in vitro and in vivo [51].

Adipose derived MSC seem not to undergo the same senescence pattern as BMMSC [66, 67]. When hAdMSC were derived from elderly (mean 71.4 years) and young donors (mean 36.4 years), cells from both age groups showed similar proliferation, osteogenic differentiation and senescence marker patterns, while BMMSC from the same cohorts showed reduced proliferation, decreased differentiation and increased senescence [66]. In concordance with these findings are data from murine AdMSC derived from senile osteoporotic SAMP6 mice, which showed maintenance of telomere leng
th, telomerase activity and osteogenic differentiation [67]. In order to determine the potency of hAdMSCs isolated from donors aged thirty, forty and fifty, their proliferation and differentiation potential to neural cells was investigated [5]. It was demonstrated that cell number, viability, morphology and neural differentiation potential were not different between hAdMSC of different age and passage. The results suggest that autologous adipose derived stem cells from aged people may be applied for stem cell therapy of age-dependent neural disease with the same stem cell quality and ability as stem cells derived from younger patients.

After i.v. delivery, MSCs are generally found at low or very low frequencies in most target organs, as shown by histology, polymerase chain reaction or by immunohistochemistry [6870]. Deak et al. [71] performed systematic kinetic assessments in non-injury models using enhanced green fluorescent protein transfected murine MSCs. They demonstrated that 24 hr after MSC application, the most frequently positive organs were lungs, liver, kidney, skin, and gut among investigated tissues. In baboons, Devine et al. [69] demonstrated that high concentration of transplant specific DNA was observed in gastrointestinal tissues. They also showed that kidney, lung, liver, thymus, and skin have relatively high amounts of DNA equivalents. Based on their studies, levels of engraftment in these tissues were estimated, ranging from 0.1 to 2.7%, with similar results with autologous and allogeneic cells [69]. After systemic administration, Lee et al. [28] found 80% of the infused MSCs in the lungs of mice 15 min after infusion, whereas after 4 days the specific signal for the presence of human MSCs decreased to 0.01%. Of importance, clinical studies with systemically delivered human MSCs did not induce significant intolerance symptoms from the pulmonary or circulatory systems, while murine MSCs displayed a somewhat different behavior. Deak et al. [72] have demonstrated in a C57BL/6 syngenic murine MSCs transfusion model, that in contrast to human MSCs, murine MSCs home to lungs and might clog in the lungs.

A number of in vivo studies have shown that systemically infused MSCs could migrate to injured, inflamed tissues and exert therapeutic effects [73, 74]. BMMSCs intravenously delivered to rats following myocardial infarction localize in the infarct region and improve ventricular function, while MSCs delivered to non-infarcted rats localize to the BM [75]. Localized abdomen irradiation significantly enhances MSC homing specifically to radiation-injured tissues in mice [76]. A recent study demonstrated the homing properties of i.v. administered hAdMSCs to cell-damaged areas in an allergic rhinitis animal model [47]. The relative organ distribution of fluorescence-labeled hAdMSCs was assessed by us in brain, spinal cord, spleen, thymus, kidney, liver, lung, and heart after i.v. injection in spinal cord injury rats by fluorescence microscopy and human specific Alu PCR. In the injured region of spinal cord, a relatively high percentage of AdMSCs (13%) was found, while most cells remained in spleen (40%) and thymus (21%) [data not shown].

Numerous studies showed the involvement of chemokines or growth factors in MSCs trafficking to the injury region. The interactions of stromal cell-derived factor-1 (SDF-1)- and C-X-C chemokine receptor type 4 (CXCR4) mediated the trafficking of transplanted BMMSCs in a rat model of left hypoglossal nerve injury. In addition, BMMSCs were attracted by chemokines that are presented in the supernatants of primary cultures of human pancreatic islets culture in vitro and in vivo[77]. When we compared soluble factors by in vitro migration assay, platelet derived growth factor (PDGF)-AB and transforming growth factor-1 (TGF-1) were most potent for migration activity of hAdMSCs [78]. hAdMSCs pre-stimulated with tumor necrosis factor (TNF-) showed the highest migration activity. When analyzed by flow cytometry and reverse transcriptase-polymerase chain reaction, hAdMSC expressed C-C chemokine receptor type 1 (CCR1), CCR7, C-X-C chemokine receptor type 4 (CXCR4), CXCR5, CXCR6, EGFR (EGF receptor), FGFR1 (FGF receptor 1), TGFBR2 (TGF receptor 2), TNFRSF1A (TNF receptor 1), PDGFRA (PDGF receptor A) and PDGFRB (PDGF receptor B) at protein and mRNA levels. This study indicates that the migration of hAdMSCs is controlled by various growth factors or chemokines. Hence, modulating the homing capacity of hAdMSCs in vivo could stimulate its migration into injured sites after i.v. administration, and thereby improve their therapeutic potential.

Several characteristics may play a role for the immune regulatory capability and anti-inflammatory effects of MSCs: 1) MSCs have low immunogenicity due to low expression levels of major histocompatibility complex-I (MHC-I) and no expression of MHC-II molecules and costimulatory molecules including B7-1 (CD80), B7-2 (CD86), or CD40 [79], (2) MSCs secrete soluble factors such as interleukin (IL)-6 and macrophage-colony stimulating factor [80] and suppress the activation and proliferation of T and B lymphocytes, and interfere with differentiation, maturation and function of dendritic cells, (3) MSC release anti-inflammatory and anti-apoptotic molecules and hence may protect damaged tissues [79, 81].

Due to these properties, MSC transplantation has been used for the treatment of GVHD, and several autoimmune diseases, including autoimmune thyroditis [20], RA [17, 18] and MS [16] and implicated for allogeneic stem cell transplantation. Systemic infusion of AdMSCs controlled lethal GVHD in mice transplanted with haploidentical hematopoietic stem cell grafts when the MSCs were injected early after transplantation [15] although ongoing clinical studies with allogeneic BMMSC were not successful. Therapeutic efficacy of BMMSCs was reported in the animal model of MS [16]. In this experimental autoimmune encephalomyelitis (EAE) model, i.v. infusion of MSCs decreased clinical symptoms when MSCs were injected before or at the onset of the disease. In an experimental collagen-induced arthritis (CIA) study, a single intraperitoneal injection of BMMSCs prevented the occurrence of severe arthritis, and was associated with a decrease in serum levels of pro-inflammatory cytokines [18]. Human AdMSCs have been demonstrated to ameliorate experimental autoimmune thyroiditis via down-regulation of Th1 cytokines [20]. Systemic infusion of hAdMSCs prevented lymphocyte infiltration to thyroid glands, decreased the production of pro-inflammatory cytokines and improved Th1/Th2 balance [20]. MSCs suppressed T-cell proliferation and cytokine production in response to alloantigen and nonspecific antigen, and prolong skin graft survival in vivo [82]. In addition, MSCs inhibit function of B cells [83], natural killer cells [84] and dendritic cells [85]. The immunomodulatory function of MSC was mediated both by soluble factors [86], and by direct cell to cell interactions [87].

Whether MSC derived from patients with autoimmune diseases will have therapeutic functions after autologous transplantation in a clinical situation is controversial and has not been addressed clinically [88]. Papadaki et al. [89] showed that while BMMSCs isolated from RA patients were found to be impaired in their ability to support hematopoiesis, BMMSCs isolated from MS patients displayed normal ability [89, 90]. Other data demonstrated that BMMSCs derived from patients with RA, MS, autoimmune SLE, systemic sclerosis (SSc) and Sjogren’s syndrome retained their immunomodulatory capabilities in vitro [91, 92].

Given their confirmed in vivo safety and the rationale
that MSCs possess immunomodulatory and anti-inflammatory properties, compassionate-use treatments for autoimmune diseases were initiated in patients after other treatment options were exhausted. All patients provided informed consent to the treatment. Here, we describe treatment of AdMSCs in autoimmune hearing loss (AIED), MS, PM, AD and RA. Details on the patients disease and treatment histories, disease status and treatments are provided in Table

and Additional File

; Case Reports, Table S1 and Figure S1. Additional clinical scores for AD before and after treatment are shown in Table

. Patient analysis was based mostly on clinical parameters. In some cases, immunological and blood status parameters were also measured (cases 3, 4, 5, 8, 9, 10); all cases showed decrease in inflammatory responses and eosinophil counts.

Summary of hAdMSC treatments of 10 patients with different autoimmune-associated diseases.

Autoimmune inner ear disease (AIED)

AIED [93, 94]is a progressive, bilateral yet asymmetric, sensorineural hearing loss. Patients have higher frequencies of interferon (IFN)-c-producing T cells and higher serum antibody titres compared with healthy controls and patients with noise- and/or age-related hearing loss [95]. The mainstay treatment for AIED are anti-inflammatory drugs, particularly corticosteroids [96, 97]. However, some patients are refractory to steroid treatment. Thus, alternative treatment is needed for these patients. Efficacy of hAdMSCs on experimental autoimmune hearing loss (EAHL) was shown in mice [98]. Mice were immunized with -tubulin to develop EAHL and treated with i.v. injection of hAdMSCs (once a week for 6 consecutive weeks) resulting in improved hearing, hair cell stabilization, reduced proliferation of antigen-specific Th1/Th17 cells and induced anti-inflammatory cytokine IL-10 in splenocytes, induction of antigen-specific CD4(+) CD25(+) Foxp3(+) regulatory T-cells with the capacity to suppress autoantigen-specific cytotoxic T-cell responses.

1

19/F

3x each 2 108 (i.v.)

6 108

Severe progressing hearing loss for 3 years (no in left ear, severe in right ear)

Normal hearing in right ear, moderate hearing in left ear

11

Multiple Sclerosis (MS)

MS is a multifocal inflammatory disease of the central nervous system, which mainly affects young women between ages twenty and forty years and causes paralysis of the limbs, sensation, visual and sphincter problems. The disease is clinically evident with relapses of neurological disability due to damage of myelin occurs (plaques of sclerosis). The disease enters a progressive phase due to damage of the axons and irreversible neurodegeneration. Existing immunotherapies downregulate the autoimmune anti-myelin reactivity and reduced the rate of relapses (e.g. INF-, glatiramer acetate and mitoxantrone) but progression of disability and myelin regeneration is not possible [99, 100]. In the chronic EAE animal model [101], BMMSCs and AdMSCs were shown to restore neuronal activity and produce new neurons [102, 103]. We demonstrated previously that hAdMSCs ameliorates the symptoms in EAE in a dose- and time-dependent manner, and these effects can be mediated in part by the production of anti-inflammatory cytokines [104].

2

46/F

5x each 1 108 (i.v.)

3x each 1 107 (intrathecal)

1.03 109

EDSS* 8

EDSS 7

4

Polymyositis

PM is a type of chronic inflammatory myopathy with unknown etiology associated with invasion of white blood cells in muscle tissue. PM is related to dermatomyositis and inclusion body myositis. Clinical signs include pain with proximal muscle weakness and loss of muscle mass, particularly in the shoulder and pelvic girdle. Despite the uncertainty in the exact cause of PM, autoimmune, viral, infectious or genetic factors have been suggested. The estimated annual incidence rate is around 5-10 cases/1, 000, 000 in the United States; it increases with age, with the highest rates seen in the 35-44 and 55-64 years. Women are two times more likely to suffer from PM than men. Corticosteroids and immunosuppressant agents are the mainstay of treatment, with a significant percentage of non-responders and clinical relapses [105]. Hematopoietic stem cell transplantation is performed in patients with refractory PM with satisfactory clinical efficacy [106], but the condition regimen for the procedure has many side effects. Allogeneic MSCs from bone marrow and umbilical cord were transplanted in 10 patients with drug-resistant PM [107]. Although none of the patients stopped immunosuppressive therapy for more than 1-year’s follow-up and there was no cure, MSCs treatment may prove to be a useful adjunctive treatment in patients whose disease is poorly controlled with immunosuppressive agents.

3

35/F

4x each 5 108 (i.v.)

2 109

inability to walk slope and to stand up by herself

Able to step up stairs (

3

Atopic Dermatitis

AD is a common, chronic and refractory skin disease manifesting as eczema and pruritus with repeated exacerbations and regressions and unknown pathogenesis [108]. The incidence of AD in adults has increased worldwide over the past decade [109]. Current management aims to relieve frequency of dermal inflammation and prevent its flare-up using topical corticosteroids and tacrolimus [109, 110]. Although these treatments
might control the symptoms, relapse is frequent and extensive and prolonged use of corticosteroid carries risk of side-effects, including skin atrophy and there are many AD patients with corticosteroid phobia [111]. Despite the immunomodulating effect of MSC, there is no previous record of stem cell treatment of AD.

4

27/F

3x each 2 108 (i.v.)

6 108

SCORAD index 93.1

SCORAD* index 61.1

5.5

5

33/M

3x each 2 108 (i.v.)

6 108

SCORAD index 57.0

SCORAD index 35.5

4.5

6

27/F

5x each 2 108 (i.v.)

1 109

SCORAD index 33.4

SCORAD index 16.4

3.5

7

26/F

3x each 2 108 (i.v.)

6 108

SCORAD index 39.1

SCORAD index 13.3

2

Rheumatoid Arthritis

RA is a T-cell-mediated systemic autoimmune disease caused by loss of immunologic self tolerance and characterized by synovium inflammation and articular destruction. MSCs were reported to reduce inflammatory and T cell responses and induce antigen specific regulatory T cells in vitro in rheumatoid arthritis [112]. Systemic infusion of hAdMSCs significantly reduced the incidence and severity of experimental arthritis induced by CIA in vivo [113], which was mediated by down-regulating Th1-driven autoimmune and inflammatory responses and induction of interleukin-10 in lymph nodes and joints. Human AdMSCs also induced de novo generation of antigen-specific CD4+CD25+FoxP3+ Treg cells. The best therapeutic benefits were seen when the stem cell treatments were performed prior to onset and by systemic rather than local application. Recently, the therapeutic effects of systemic infusion human umbilical cord (UC)-MSCs were also verified in the collagen-induced arthritis model [114]with effects similar to those of hAdMSCs.

8

50/F

2x each 3 108 (i.v.)

6 108

***VAS score: 10 KWOMAC score: 73

VAS score:2-3 KWOMAC score: 28

7

9

51/F

Once 2 108

(i.v.) + 1 108

(intrarticular)

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Stem cell treatment for patients with autoimmune disease …

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visit the mesenchymal cell research webpage – stemcell.com

Posted: July 20, 2016 at 8:42 pm

Mesenchymal stem cells (MSCs) are fibroblast-like cells isolated from bone marrow, adipose, and other tissues – including cord blood, peripheral blood, fetal liver, skeletal muscle, placenta, amniotic fluid and synovium.1-7See MoreThese are all vascularized tissues, and accumulating evidence suggests that MSCs are pericytes8 which closely encircle endothelial cells in capillaries and microvessels of multiple organs.8-15

MSCs are defined by properties exhibited following in vitro culture. Namely the ability to self-renew, differentiate into bone, adipose and cartilage tissue,16 the expression of CD105, CD73 and CD90, and the lack of expression of CD45, CD34,CD11b and HLA-DR. While originally coined mesenchymal stem cells,17 MSCs are also referred to by other terms, such as multipotent mesenchymal stromal cells,16,18 mesenchymal progenitor cells19 or medicinal signaling cells.20 No single term has been uniformly adopted, and as a result, the acronym MSC is commonly used to encompass all terminologies applied to these cells.

MSCs have potential utility in a range of cellular therapies, with applications relating to tissue engineering and regenerative medicine, and as vehicles for gene therapy.21-24 To realize the therapeutic potential of MSCs, studies in animal models are of fundamental importance. Because MSCs are rare, occurring at an estimated frequency of 1 in 100,000 cells in adult human bone marrow, they must be expanded in vitro to obtain sufficient numbers for research and therapeutic applications.25 The ability to expand human MSCs in xeno-free or animal component-free medium may alleviate concerns about immune rejection of transplanted cells or disease transmission, and is therefore an important consideration when the MSCs are to be used therapeutically.25

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Mesenchymal Stromal Cells

Posted: July 3, 2016 at 7:44 pm

Curr Opin Hematol. Author manuscript; available in PMC 2012 Jun 1.

Published in final edited form as:

PMCID: PMC3365862

NIHMSID: NIHMS16948

Mesenchymal stromal cells (MSCs) are the spindle shaped plastic-adherent cells isolated from bone marrow, adipose, and other tissue sources, with multipotent differentiation capacity in vitro. However, whether MSCs truly qualify as stem cells is an area of some debate[1]. MSCs were first described by Friendenstein as hematopoietic supportive cells of bone marrow. He showed that MSCs could differentiate to bone in vitro and a subset of the cells had a high proliferative potential (CFU-F) when plated at low density in tissue culture[2,3]. Based largely on Friendensteins work, Maureen Owen proposed the existence of a stromal stem cell to maintain the marrow microenvironment as the hematopoietic stem cell maintains hematopoiesis[4]. The notion of a mesenchymal stem cell was popularized by Arnold Caplan proposing that MSCs gave rise to bone, cartilage, tendon, ligament, marrow stroma, adipocytes, dermis, muscle and connective tissue[5]. However, convincing data to support the stemness of these cells were not forthcoming, and now most investigators recognize that in vitro isolated MSCs are not a homogenous population of stem cells, although a bona fide mesenchymal stem cell may reside within the adherent cell compartment of marrow[6].

MSCs undoubtedly play a critical role in the marrow microenvironment. Following intramedullary transplantation of eGFP-marked human MSCs into a NOD SCID mouse, the MSCs incorporated into the murine marrow microenvironment and improved the human hematopoietic stem cell activity in the host mouse[7]. MSCs are also thought to be of great value for cell based therapies. This discussion will focus on the properties of MSCs that engender their utility as therapeutic cells and specifically on MSCs as treatment for GVHD and as targeting vehicles for anti-tumor therapies.

As stated above, data to support the designation of MSCs as biologically functional stem cells are lacking. However, the acronym, MSC, is firmly engrained in the vernacular of cell biologists and clinical cell therapists. Thus, the International Society for Cellular Therapy (ISCT) has recommended that these spindle-shaped, plastic-adherent cells be termed, mesenchymal stromal cells [6]. This label allows investigators to continue to use the acronym, MSCs, which should reduce the potential for confusion in the literature. A biologically active stem cell for mesenchymal tissues may exist, but the term mesenchymal stem cell should be reserved for the subset of mesenchymal cells that demonstrate stem cell activity by rigorous criteria.

The defining characteristics of MSCs are inconsistent among investigators due, in part, to the lack of a universally accepted surface marker phenotype. However, all proposed MSC populations are plastic adherent in vitro; hence, this is one defining characteristic. The first important studies of surface antigen markers led to the development of SH2 and SH3, antibodies which seemed to identify MSCs[8]. Subsequently, SH2 and SH3 were shown to recognize epitopes on CD105 and CD73, respectively[9,10]. Furthermore, CD90 is expressed on all cells that we accept as MSCs. These cells do not express hematopoietic antigens, e.g. CD45, CD34, CD14, CD19, or CD3. Additionally, MSCs express MHC Class I molecules in vitro, but not Class II molecules unless stimulated, e.g. by interferon, in tissue culture. Thus, a surface marker phenotype of MSCs is CD105+, CD73+, CD90+, CD45, CD34 CD14, CD19, CD3, HLA DR. While unequivocally identifying MSCs, this surface marker profile is cumbersome. Stable, pancellular expression of surface markers that are unique to MSCs within the bone marrow, the most common source of MSCs, would greatly facilitate the identification of these cells.

The single most characteristic feature of MSCs is the capacity to differentiate to osteoblasts, adipocytes, and chondroblasts in vitro. It is therefore quite reasonable for investigators to demonstrate such trilineage differentiation in vitro to prove their cells under study are MSCs.

In practice, MSCs can be defined by the criteria shown in the Table, as proposed by the ISCT Mesenchymal and Tissue Stem Cell Committee[11]. The criteria are designed not only to define the MSCs, but also to exclude hematopoietic cells, which is important since, as stated above, MSCs are most commonly isolated from bone marrow. CD3 expression is not included in the criteria because T cells are uncommon contaminants of MSC preparations. It is important to avoid hematopoietic cells among the populations of MSCs being used for cell therapy studies because they could alter the scientific outcomes and may be deleterious for patients in clinical trials.

For obvious reasons, if the proposed therapeutic cells are not readily accessible, clinical utility is limited. Effective cell therapy, therefore, begins with a cell type that is relatively easy to isolate. MSCs are most often isolated by adherence selection. For example, bone marrow mononuclear cells are placed in a plastic tissue culture vessel and maintained for 15 days at 37C. Then, the nonadherent cells are removed as the media is changed and the remaining adherent cells are isolated MSCs. At this stage, the MSC cultures are definitely not free of contamination by resident tissue cells, e.g. hematopoietic cells; however, successive passages of the ex vivo expanded cells effectively remove most or all contaminating cells. Thus, tissue culture serves to expand and purify the MSCs. Similarly, when other sources of MSCs, e.g. adipose tissue, a mononuclear cell preparation is maintained in tissue culture to isolate the MSCs.

There are three fundamental questions that must be addressed when using MSCs as cell therapy for tissue regeneration. First, will MSCs differentiate to the tissue of interest in vivo? This is a critically important issue as certain culture conditions may induce atypical differentiation in vitro that may not occur in vivo. Additionally, MSCs may not differentiate to the targeted tissue, but instead generate cell types that function in a beneficial way within the tissue. For example MSCs may secrete useful soluble mediators that foster repair of a tissue so that differentiation is unneeded for clinical benefit. Thus, MSCs may be highly effective for applications in regenerative medicine by several mechanisms.

Second, how can the cells be delivered to the relevant tissue(s)? For example, if intravenously infused, will MSCs home to the desired sites? Although some investigators have suggested that MSCs home to sites of inflammation, it is unclear that MSCs home to sites of other types of local or systemic disease, and there is little data indicating that MSCs home to healthy tissue. Despite the uncertainty of homing to diseased tissues, sufficient intravenously infused MSCs may arrive and incorporate in the desired tissue to generate clinical benefits. For example, Horwitz et al. reported the infusion of MSCs after BMT into children with osteogenesis imperfecta, a metabolic bone disorder. Engraftment and growth acceleration was demonstrated in 5 of 6 patients[12]. Koc et al. reported MSC
infusion in children with metachromatic leukodystrophy and Hurlers disease after BMT. In 4 of 6 patients with metachromatic leukodystrophy, an improvement in nerve conduction velocity was observed, but engraftment in the neural tissue was not assessed[13]. In both cases, homing strictly defined was not demonstrated; however the former study showed the presence of intravenously infused cells within the targeted tissue.

Third, how much tissue replacement by donor cells (i.e. engraftment) is needed to achieve correction or improvement of the damage or diseased tissue? The answer will likely be tissue and disease specific, and therefore will require animal models that reliably model the human disease, or more effectively, pilot clinical trials. Importantly, the level of tissue replacement is often quite low, far less than what may be hypothesized; consequently, estimates are useful to determine which diseases should be investigated, but experimental data are essential to formulate therapeutic strategies.

Any cell employed for therapeutic purposes would ideally be immunoprivileged allowing for use in HLA mismatched patients. Further, cells that can regulate the immune response could be effectively used to modulate the immune system to treat immunologic disease. MSCs have been reported to be immunosuppressive and immunoprivileged. The two terms are often used interchangeably; however, this is strictly incorrect. A cell may escape immune recognition (i.e. immunoprivileged) without having an effect on immune effector cells. Similarly, a cell may secrete immunosuppressive molecules while being recognized by an allogeneic immune system. MSCs do seem to exhibit an effect on the immune effector cells in vitro. This property has led to much dialogue whether MSCs could be effective therapy for autoimmune diseases such as rheumatoid arthritis. More important for this discussion is the role of MSCs in the treatment Graft-versus-Host Disease (GVHD).

As mentioned above, MSCs are an essential component of the stromal scaffold of the bone marrow that provides physical and functional support during hematopoiesis. Based on this concept, MSCs have been studied for their ability to improve engraftment of hematopoietic stem cells in vivo[14, 15]. While some reports suggest that MSCs increase engraftment, the data are not particularly impressive, at least in the models utilized. It has been recently shown that MSCs exert a profound immunomodulatory effect by means of both soluble and cell contact-dependent mechanisms[16]. MSCs can act both on T and B cells and although several mechanisms of action have been suggested, the data are contradictory. The ability to inhibit or stimulate T-cell alloresponses appears to be independent of HLA matching. It is still unclear whether MSCs naturally exhibit an immunoregulatory role or whether this is the consequence of a more general, non-specific interference with the cell cycle[17].

In this context, it is interesting to note that stromal cells, together with osteoblasts and endothelial cells, contribute to the formation of the HSC niche. This can be defined as a specialized microenvironment that precisely maintains a long-term storage of quiescent, slowly dividing HSCs by preventing their proliferation, differentiation or apoptosis. It can be hypothesized that MSCs, on one hand, are preventing T lymphocyte activation and proliferation (to prevent possible harm on HSC) and, on the other hand, seem to exert a potent anti-apoptotic effect. Although the mechanisms of immunomodulation are still unfolding, a relevant in vivo immunomodulatory effect has been shown: 1) if given in patients with severe acute GVHD, they are able to reverse the evolution of GVHD in a significant proportion of patients[18, 19], and 2) in a recent in vivo experiment in which injection of MSCs ameliorated the course of chronic progressive experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis[20].

The EBMT MSC Expansion Consortium used MSCs to treat grades IIIIV GVHD in 40 patients who were resistant to second line GVHD treatment. The MSC dose was a median 1.0 x 106 cells/kg recipient body weight (range 0.49 x 106 cells/kg). Adverse effects were not seen after MSC infusions. Nineteen patients received one dose, 19 patients received 2 doses, one patient received 3 doses, and one patient received 5 doses. In some cases, an individual patient received MSC doses from different donors. The MSC donors were HLA-identical siblings in 5 cases, haploidentical donors in 19 cases, and 41 cases of third-party HLA-mismatched donors. Among the 40 patients treated for severe acute GVHD, 19 had complete responses, 9 showed improvement, 7 did not respond, 4 had stable disease and 1 was not evaluated due to short follow-up. Ectopic tissue formation was not seen. MSC dramatically affected tissue repair of severe acute GVHD of the gut, liver, and skin in a consistent proportion of patients. Twenty-one patients are alive with between 6 weeks and 3.5 years follow-up after transplantation. Nine of these patients have extensive chronic GVHD. One patient with ALL has recurrent leukemia and one patient has de novo AML of host origin. In view of the dismal outcome in patients with grades IIIIV acute GVHD, the data from this small trial are promising. However, the optimal strategy for the treatment of GVHD based on MSC infusion has not yet been determined and remains rather complex for a several reasons: 1) the ex vivo cell expansion is expensive and time consuming; 2) there is variation in the expansion capability from donor to donor; 3) often, previously expanded MSCs are required for the timely treatment of GVHD; 4) the optimal dose of MSCs, or the need for multiple infusions, to obtain the maximal effect on GVHD is unknown; 5) expanded MSCs are very difficult to detect after infusion, and the patients marrow stroma remain of host origin with the possible exception of some pediatric patients.

Ongoing efforts within the EBMT Consortium are addressing these challenges in an effort to determine the role of MSC therapy in the treatment for GVHD. At the current state of research, we conclude that MSCs have both immunomodulatory and tissue repairing effects and should be further explored as treatment of severe acute GVHD in prospective randomized trials.

The formation of stroma is essential for tumor growth and involves complex interactions between malignant tumor cells and non-tumor stromal cells. Studeny et al. have demonstrated that MSCs integrate into solid tumors, suggesting the development of anti-cancer therapies based on the intratumoral production of agents by gene-modified MSCs[2123].

Andreeff and colleagues have now conducted a series of experiments to address this issue by noninvasively visualizing MSCs using luciferase bioluminescence. The cells were labeled by a fiber modified adenoviral vector expressing firefly luciferase (AdLux-F/RGD) and the MSC-Lux were injected into normal (healthy) SCID mice or mice bearing established metastatic breast or ovarian tumors. Biodistributed MSC-Lux were imaged utilizing the Xenogen IVIS detection system. In normal mice, human MSC (hMSC) migrated to the lungs where they remained resident for 710 days. In animals bearing established metastatic lung tumors, IV injected hMSC again migrated to the lungs. However, in contrast to control mice, the Lux signal remained
strong over a 15-day period with only a slight decrease over the first 10 days. After IP injection, hMSC-LUX were detected in the peritoneum, and after 7 days, no hMSC-LUX was detected in normal animals, while strong punctate regions of LUX-activity were observed in ovarian tumors. In contrast to SCID mice injected with hMSC, when healthy Balb/C mice were injected, Balb/C derived MSC-LUX initially migrated to the lungs, but within 2.5 hrs had exited the lungs to remain liver and spleen resident for 57 days. Tumor cells were then transduced with renilla luciferase constructs allowing for the co-localization and dynamic interactions of firefly luciferase MSCs and renilla luciferase tumors to be demonstrated.

hMSC-producing interferon-beta (IFNb-MSC) were found to inhibit the growth of metastatic tumors in the lungs of SCID mice. When injected IV (4 doses of 106 MSC/week) into SCID mice bearing pulmonary metastases of carcinomas or melanomas, tumor growth was significantly inhibited as compared to untreated or vector-control MSC controls (p= 0.007), while recombinant IFNb protein (50,000 IU qod) was ineffective (p=0.14). IV injected IFNb-MSC prolonged the survival of mice bearing metastatic breast carcinomas (p=0.001). Intraperitoneal (IP) injections of IFN-MSC into mice carrying ovarian carcinomas resulted in doubling of survival in SKOV-3, and cures in 70% of mice carrying OVAR-3 tumors.

A similar strategy is also effective as therapy for brain tumors. MSC injected into the ipsilateral or contralateral carotid artery were found to localize to glioma xenografts in mice and IFNb-MSC significantly (p

These data suggest that systemically administered gene-modified MSC selectively engrafts into the tumor microenvironment and remain resident as part of the tumor architecture. MSC-expressing IFN-b inhibit the growth of melanomas, gliomas, metastatic breast and ovarian cancers in vivo and prolong the survival of mice bearing established tumors. Thus, MSCs are potentially a universal vehicle to deliver localized antitumor therapy. Clinical trials, which are in development, will be conducted to test these experimental findings.

MSCs have an enormous potential as cell therapy in tissue regeneration, immune modulation, and as delivery vehicles for the specific delivery vehicles for anti-tumor agents, but the true clinical utility remains to be proven. MSCs are relatively easy to isolate and purify, and we currently have means to unequivocally identify the cells, although more specific surface markers are needed. MSCs have been infused into well over a hundred patients, including young children, without serious adverse events testifying to the general safety of this strategy. Future efforts in our field must focus on better defining the therapeutic potential of MSCs through clinical trials and better understanding of the biology of MSCs to elucidate the mechanisms of these therapeutic effects.

Table. Summary of Criteria to Identify Mesenchymal Stromal Cells (MSCs).

Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

23. Marini F, Hall B, Dembinski J, Studeny M, Sasser AK, Andreeff M. Mesenchymal stem cells as vehicles for genetic targeting of tumors. In: Ho AD, Hoffman R, Zanjani ED, editors. Stem Cell Transplantation. Wiley-VCH Verlag; Weinheim, Germany: 2006. pp. 157175.

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Mesenchymal Stromal Cells

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Immunosuppression by mesenchymal stem cells: mechanisms and …

Posted: at 7:44 pm

Stem Cell Research & Therapy20101:2

DOI: 10.1186/scrt2

BioMed Central Ltd2010

Published: 15March2010

Mesenchymal stem cells (MSCs) are multipotential nonhematopoietic progenitor cells that are isolated from many adult tissues, in particular from the bone marrow and adipose tissue. Along with their capacity for differentiating into cells of mesodermal lineage, such as adipocytes, osteoblasts and chondrocytes, these cells have also generated great interest for their ability to display immunomodulatory capacities. Indeed, a major breakthrough came with the finding that they are able to induce peripheral tolerance, suggesting they may be used as therapeutic tools in immune-mediated disorders. The present review aims at discussing the current knowledge on the targets and mechanisms of MSC-mediated immunosuppression as well as the potential use of MSCs as modulators of immune responses in a variety of diseases related to alloreactive immunity or autoimmunity

Mesenchymal stem cells (MSCs), also named multipotent mesenchymal stromal cells, are largely studied as new therapeutic tools for a number of clinical applications. Indeed, these cells have been shown to have differentiation capacities as well as paracrine effects via the secretion of growth factors, cytokines, antifibrotic or angiogenic mediators [1]. A large body of studies also indicates that MSCs possess an immunosuppressive function both in vitro and in vivo. We review the present knowledge on the mechanisms underlying the immunomodulatory characteristics of MSCs and their applications in animal models of immune suppression or in clinics.

MSCs were initially isolated from bone marrow but are now shown to reside in almost every type of connective tissue [2]. MSCs are characterized as a heterogeneous population of cells that proliferate in vitro as plastic-adherent cells able to develop as fibroblast colony forming-units [3]. MSCs are distinguished from hematopoietic cells by being negative for the cell surface markers CD11b, CD14, CD34, CD45 and human leukocyte antigen (HLA)-DR but expressing CD73, CD90 and CD105. Importantly, the capacity to differentiate into multiple mesenchymal lineages including bone, fat and cartilage is used as a functional criterion to define MSCs [4].

MSC-mediated immunosuppression requires preliminary activation of the MSCs by immune cells through the secretion of the proinflammatory cytokine IFN, alone or together with TNF, IL-1 or IL-1 [5, 6]. This activation step has also been shown in vivo in a model of graft versus host disease (GVHD) since recipients of IFN-/- T cells did not respond to MSC treatment and succumbed to GVHD [7]. Indeed, MSCs from mice deficient for the IFN receptor 1 do not have immunosuppressive activity, highlighting the important role of IFN in this process [6].

Although target cell-MSC interactions may play a role, the MSC-mediated immunosuppression mainly acts through the secretion of soluble molecules that are induced or upregulated following cross-talk with target cells. Among these factors, indoleamine 2,3-dioxygenase (IDO) has consistently been reported [8, 9]. On stimulation with IFN, this enzyme metabolizes tryptophan to kynurenin, causing depletion of local tryptophan and accumulation of toxic breakdown products. IDO, however, exerts its effects mainly through the local accumulation of tryptophan metabolites rather than through tryptophan depletion [10]. Whereas the majority of studies indicate a potentially important function for IDO, human MSCs lacking both IFN receptor 1 and IDO still exerted important immunomodulatory activity [11]. This observation may be explained at least in part by a recent study reporting that Toll-like receptors expressed on MSCs augment their immunosuppressive activity in the absence of IFN through an autocrine IFN signaling loop, which was dependent on protein kinase R and able to induce IDO [12]. Contrary to human MSCs, lack of IDO activity was constantly reported for murine MSCs [13, 14].

Induction of inducible nitric-oxide synthase (iNOS) by murine MSCs and production of nitric oxide was suggested to play a major role in T-cell proliferation inhibition [15]. Nitric oxide is a gaseous bioactive compound affecting macrophage and T-cell functions. iNOS is induced in mouse MSCs after activation by IFN and TNF, IL-1 or IL-1, and MSCs from iNOS-/- mice had a reduced ability to suppress T-cell proliferation [6] (Bouffi C, Bony C, Courties G, Jorgensen C, Nol D, submitted). The expression level of iNOS mRNA in human MSCs was minimal [14], however, and secretion of nitric oxide by human MSCs was undetectable (Bouffi C, Bony C, Courties G, Jorgensen C, Nol D, unpublished results). Indeed, different mechanisms of immunosuppression exist in different species since human MSCs employ IDO as a major effector molecule whereas nitric oxide plays a critical role in mouse MSCs [14].

Prostaglandin E2 (PGE2) has also been involved in the immunosuppressive activity of MSCs. PGE2 is a product of arachidonic acid metabolism that acts as a powerful immune suppressant, inhibiting T-cell mitogenesis and IL-2 production, and is a cofactor for the induction of T-helper (Th) type 2 lymphocyte activity. Production of PGE2 by MSCs is enhanced following TNF or IFN stimulation, and its inhibition using specific inhibitors resulted in restoration of T-lymphocyte proliferation [16]. MSC-derived PGE2 was shown to act on macrophages by stimulating the production of IL-10 and on monocytes by blocking their differentiation toward dendritic cells (DCs) [17, 18].

Another MSC-secreted factor, IL-6, has been reported to be involved in the inhibition of monocyte differentiation toward DCs, decreasing their stimulation ability on T cells [13, 19]. In parallel, the secretion of IL-6 by MSCs has also been reported to delay apoptosis of lymphocytes and neutrophils [20, 21].

Other mediators – such as transforming growth factor beta 1, hepatocyte growth factor, heme oxygenase 1 and leukemia inhibitory factor – were shown to be produced by MSCs upon activation [16, 2224]. The production of HLA-G5 by MSCs has more recently been shown to suppress T-cell proliferation, as well as natural killer cell cytotoxicity and T-cell cytotoxicity, and to promote the generation of regulatory T (TREG) cells [25, 26]. Cell contact between MSCs and activated T cells induced IL-10 production, which was essential to stimulate the release of soluble HLA-G5.

Any of these molecules alone does not lead to a complete abrogation of T-cell proliferation, indicating their nonexclusive role. Instead, MSC-mediated immunoregulation is the result of the cumulative action displayed by several molecules.

Both CD4+ and CD8+ T-lymphocyte proliferation stimulated with mitogens or specific antigens is suppressed by MSCs. Suppression occurred with MSCs from autologous or allogeneic sources, indicating that it was not restricted by major histocompatibility complex (MHC) [27, 28]. Inhibition of proliferation depends on the arrest of T cells in the G0/G1 phase of the cell cycle, independently of apoptosis, but instead MSCs promote the survival of stimulated T cells [29, 30]. MSCs alter other T-cell functions, such as the decrease of production of IFN
, IL-2, and TNF and the increase of IL-4 secretion [16]. MSCs are not targets of CD8+ cytotoxic T cells but they can suppress the cytotoxic effects of cytotoxic T cells [31]. Finally, MSCs have been reported to promote, both in vitro and in vivo, the generation of CD4+CD25+ or CD8+ TREG cells with functional properties [32]. In vivo data, however, are contradictory [33, 34]. Recent studies suggest that MSCs may induce a cytokine profile shift in the Th1/Th2 balance toward the anti-inflammatory phenotype Th2 [35, 36] (Bouffi C, Bony C, Courties G, Jorgensen C, Nol D, personal communication). Indeed, MSCs can suppress antigen-specific T-cell proliferation and cytotoxicity as well as inducing anti-inflammatory or TREG cells.

Most studies have reported that MSCs inhibit the proliferation of B cells that are activated with anti-immunoglobulin antibodies, soluble CD40 ligand or cytokines [37]. Nevertheless, activated B cells became susceptible to the suppressive activity of MSCs in the presence of exogenously added IFN [5]. The suppressive effect of IFN was possibly related to its ability to stimulate the production of IDO by MSCs, which in turn suppressed the proliferative response of effector T cells. MSCs exert their suppressive effect on B-cell terminal differentiation through the release of humoral factor(s); they also increase B-cell viability while inhibiting proliferation, arresting B lymphocytes in the G0/G1 phase of the cell cycle [38, 39]. Another study, however, reported that MSCs promoted proliferation and differentiation of transitional and naive B cells into immunoglobulin-secreting cells, and strongly enhanced proliferation and differentiation of memory B-cell populations into plasma cells [40]. Again, differences in cell purification procedures, experimental conditions and timing of analysis may explain discrepancies between studies.

Myeloid DCs are the most potent antigen-presenting cells, essential in the induction of immunity and tolerance. During maturation, immature DCs acquire the expression of co-stimulatory molecules and upregulate the expression of MHC class I and class II molecules together with other cell surface markers such as CD11c, CD80, CD83 and CD86. MSCs inhibit in vitro the maturation of monocytes and CD34+ hematopoietic progenitor cells into DCs, as shown by a decreased cell-surface expression of MHC class II and co-stimulatory molecules, as well as a decreased production of IL-12 and TNF [16, 19, 41]. This effect is at least partially mediated via the secretion of IL-6 by activated MSCs [13, 19] or PGE2, which was directly responsible for blocking DC maturation [18]. These studies suggest that MSCs might direct DC maturation toward an anti-inflammatory or regulatory phenotype responsible for an attenuated T-cell response.

Natural killer cells exhibit cytolytic activity that mainly targets cells which lack expression of HLA class I molecules. Killing by natural killer cells is regulated by a balance of signals transmitted by activating and inhibitory receptors interacting with HLA molecules on target cells. MSCs have been shown to suppress IL-2-driven or IL-15-driven natural killer cell proliferation, IFN production and cytotoxicity against HLA class I-expressing targets [42]. Some of these effects seem to depend on cell-to-cell contact and on the release of soluble factors, including transforming growth factor beta 1 and PGE2, suggesting the existence of diverse mechanisms for MSC-mediated natural killer cell suppression.

Neutrophils are also important mediators of innate immunity responsible for microorganism killing via the production of reactive oxygen species. MSCs were shown to delay apoptosis of neutrophils through an IL-6-mediated mechanism that was associated with the downregulation of reactive oxygen species [20]. Delayed apoptosis was thought to preserve the pool of neutrophils that will be rapidly available in response to infections. Recently, Nemeth and colleagues suggested that LPS and TNF stimulated MSCs during sepsis to secrete high levels of PGE2, which in turn reprogrammed monocytes and macrophages to produce large amounts of IL-10. The released IL-10 seemed to prevent neutrophils from migrating into tissues and causing oxidative damage, thus mitigating multiorgan damage [17]. The results therefore suggest that MSCs may modulate the host innate response and improve survival by preventing sepsis.

The various studies indicate that MSCs suppress the function of several immune cells; notably the proliferation of T lymphocytes, the DC maturation and the induction of anti-inflammatory or T

cells. Some mechanisms of immunomodulation have been reproduced by several groups, in particular the secretion of IDO, PGE

, nitric oxide and HLA-G5 (Figure

). Differences in the secretome profile – particularly for IDO and nitric oxide – exist between humans and mice, however, suggesting that several mechanisms are likely to be responsible for the various effects reported to date. Our recent data suggest that MSCs exert two levels of action (Bouffi C, Bony C, Courties G, Jorgensen C, Nol D, personal communication). One level occurs locally via the secretion of mediators that inhibit the proliferation of immune cells at the vicinity of MSCs. The second induces a systemic response, either an anti-inflammatory Th2 immune profile or, in some instances, the generation of T

cells.

Schematic representation of the interactions between mesenchymal stem cells and immune cells. After activation, mesenchymal stem cells secrete soluble mediators – such as nitric oxide (NO), prostaglandin (PGE2), indoleamine 2,3-dioxygenase (IDO), IL-6, and human leukocyte antigen (HLA)-G. Production of these mediators regulates the proliferation and function of a variety of immune cells as well as the induction of regulatory T (TREG) cells either directly or indirectly through the generation of immature dendritic cells (DC). NK, natural killer.

The trafficking and homing properties of MSCs are of particular interest for clinical applications aiming at using non-invasive systemic cell administration to treat inflammation. MSCs have been shown to express a variety of chemokines and chemokine receptors and can home to sites of inflammation by migrating towards inflammatory chemokines and cytokines [43, 44]. Depending on the studies, heterogeneity in surface receptor expression is observed – which is probably due to differences in culture conditions and limitations in detection techniques. Homing of cultured MSCs, however, is inefficient compared with leukocytes. This inefficiency has been attributed to a lack of cell adhesion and chemokine receptors but also to the size of MSCs that promote passive cell entrapment and reduce trafficking [45]. Together with the evidence that host MSCs can mobilize in response to inflammation or injury, systemically infused MSCs are also frequently observed within the bone marrow or in injured tissues. Indeed, although the understanding of the underlying mechanisms is still required, accumulating evidence suggests that systemic infusion of MSCs may be used for immunosuppressive treatments of various disorders.

The hypoimmunogenicity of MSCs supports their therapeutic
interest in a variety of diseases related to alloreactive immunity or autoimmunity. Indeed, the poor immunogenicity of these cells demonstrated in vitro and in vivo favors the possible use of allogeneic MSCs in acute clinical conditions where the availability of sufficient numbers of cells is rapidly needed. The use of autologous cells, however, may have therapeutic applications in autoimmune diseases or pathologies that allow enough time for isolation and in vitro expansion of MSCs. The few clinical applications performed to date confirm safety with a lack of major adverse side effects. Indeed, serial magnetic resonance imaging performed in 226 patients who received MSCs for various orthopedic conditions showed no evidence of malignant transformation for a mean follow-up of 10.6 7.3 months [46]. Accordingly, although some studies described the capacity of human MSCs to accumulate chromosomal instability in vitro, it was recently reported that, even though some aneuploidy was detected, MSCs showed progressive growth arrest and entered senescence without evidence of transformation either in vitro or in vivo [47]. Further studies are needed, however, to address the in vivo survival of MSCs, ectopic tissue formation and malignant transformation on a larger number of cell preparations.

One of the first in vivo studies showed that systemic infusion of MSCs isolated from bone marrow prolonged the survival of allogeneic skin grafts from 7 to 11 days in baboons receiving MSCs [48]. Using a semi-allogeneic heart transplant mouse model, infusion of donor-derived MSCs prolonged cardiac allograft survival through tolerance induction, which was due to CD4+ CD25+Foxp3+ TREG cell expansion and impaired anti-donor Th1 activity [49].

In hematopoietic stem cell (HSC) transplantation, MSCs may help reconstitution of the bone marrow stroma after chemoradiotherapy and enhance HSC engraftment. As early as 2000, autologous MSC infusion was shown to improve the outcome of HSC transplantation in advanced breast cancer patients [50]. Infusion of allogeneic MSCs, contrary to syngeneic MSCs, has since been demonstrated to result in rejection of stem cell grafts in a murine model of allogeneic bone marrow transplantation [51]. The results in animal models on the potential use of MSCs to prevent rejection of allogeneic grafts are conflicting (for a review, see [52]). In a more recent study, however, co-transplantation of donor MSCs with HLA-disparate CD34+ HSCs resulted in sustained hematopoietic engraftment in 14 children without any adverse reaction, indicating that MSCs reduce the risk of graft failure in haplo-identical HSC transplant recipients [53].

MSC infusion may also be very helpful in cord blood transplantation where the limited dose of stem cells delays engraftment and favors graft failure. This cell therapy approach has also been used as GVHD prophylaxis in HSC transplantation.

The most significant results on the immunosuppressive effects of MSCs so far have been observed in the treatment of acute GVHD after allogeneic stem cell transplantation. GVHD occurring beyond 100 days after HSC transplantation is generally called chronic GVHD, which has to be distinguished from acute GVHD that includes persistent, recurrent, or late-onset acute GVHD.

The first case of ex vivo expanded haplo-identical MSC injection in a patient with severe grade IV GVHD of the gut and liver resulted in a striking improvement of the disease [54]. A phase II study has since reported that 30 out of 55 patients had a complete response and nine patients showed improvement, indicating that, irrespective of the donor, MSC infusion might be an effective therapy for patients with steroid-resistant, acute GVHD [55]. Another report on patients with leukemia, however, showed effective prevention of acute GVHD but a higher incidence of relapses in patients who were co-transplanted with MSCs and MHC-identical allogeneic HSCs [56]. Co-transplantation of third-party donor HSCs with cord blood transplants has been shown to overcome the limitation posed by low cellularity of cord blood units for unrelated transplants in adults. For optimization of this therapeutic approach, the risk of GVHD still has to be reduced. The co-infusion of MSCs from the same HSC donors was therapeutically effective for severe acute GVHD but no significant differences in cord blood engraftment and incidence of GVHD were observed [57]. The results indicate the therapeutic potential of MSCs for acute GVHD control, but underline the need for better control of safety issues.

Based on their ability to moderate T-cell proliferation and function, MSCs have also been proposed as a therapeutic option in the treatment of autoimmune diseases. They have therefore been tested in a variety of animal models of diabetes, experimental autoimmune encephalomyelitis, systemic lupus erythematosus or rheumatoid arthritis.

Contrasted results were reported in rheumatoid arthritis using the experimental collagen-induced arthritis model. We first showed that injection of the allogeneic C3H10T1/2 MSC line did not reverse the disease score [58]. In the same model, however, a single injection of primary MSCs was shown to prevent the occurrence of severe arthritis, which was associated with a decrease in serum proinflammatory cytokines [59, 60]. The use of human adipose-derived MSCs was effective in the xenogeneic collagen-induced arthritis model. The therapeutic efficacy was associated with decreased antigen-specific Th1/Th17 cell expansion, enhanced secretion of IL-10 and generation of CD4+ CD25+ Foxp3+ TREG cells with the capacity to suppress self-reactive T-effector responses [61]. Another study reported no convincing increase of TREG cells in vivo despite in vitro evidence of T-cell inhibition by MSCs [62]. Our recent data with primary syngeneic and allogeneic MSCs indicate that MSCs may have a dual effect: locally, reducing the clinical signs of inflammation in the joints, probably via the secretion of antiproliferative mediators; and systemically, by switching the polarization of the host response towards a Th2 immune profile (Bouffi C, Bony C, Courties G, Jorgensen C, Nol D, personal communication). The divergent mechanistic results obtained from the various studies underline the complexity of the MSC-mediated immunosuppressive process and the differences that may be attributed to the various MSC species used [14] and to the different techniques of MSC isolation and culture [7, 59].

In the experimental autoimmune encephalomyelitis murine model of multiple sclerosis, MSCs were shown to decrease the clinical signs associated with demyelinization when injected before or at the onset of the disease, demonstrating the therapeutic efficacy of MSCs [34]. This effect was associated with immune suppression of effector T cells leading to IL-2 reversible T-cell anergy. Subsequently, it was reported that MSCs inhibited T-cell activation with reduced IL-17 and TNF levels via the secretion of CCL2 by MSCs [63].

MSC transplantation conferred significant therapeutic effects in the systemic lupus erythematosus mouse model of lupus by reconstructing the osteoblastic niche and restoring immune homeostasis [64]. On the basis of these promising results, four treatment-refractory patients were treated with allogeneic MSCs. The patients presented a stable 12-month to 1
8-month disease remission, showing improvement in serologic markers and renal function [64]. Their data showed that MSC infusion restored the Foxp3+ cell levels in both mice and systemic lupus erythematosus patients.

Development of autoimmune diabetes results from immune cell dysfunction to maintain peripheral and central tolerance. MSCs may therefore be helpful in regulating TREG/autoreactive T-cell balance. The first results were obtained in the NOD/SCID model of chemically induced diabetes using human MSCs. In the treated diabetic mice, an increase in pancreatic islets and beta cells producing insulin was detected with a few glomerular endothelial cells of human origin. There was also a decrease in macrophage infiltration, resulting in the prevention of pancreatic injury [65]. The role of MSCs was first suggested to induce the regeneration of endogenous insulin-secreting cells, and, second, to inhibit the T-cell-mediated immune responses against newly formed beta cells [66]. A shift of the host immune response toward Th2-like responses was proposed to occur in treated NOD mice [67].

Overall, the current data indicate that MSCs represent a promising alternative strategy in the treatment of various immune-mediated diseases. Encouraging results have already been obtained from the clinics. Many questions remain to be addressed, however, in order to provide better ways to control and optimize the immune response for the benefit of the patient. This implies a better understanding of the underlying mechanisms of immunosuppression as well as satisfying safety concerns as regards the in vivo survival, formation of ectopic tissue and malignant transformation.

dendritic cell

graft versus host disease

human leukocyte antigen

hematopoietic stem cell

indoleamine 2,3-dioxygenase

interferon

interleukin

inducible nitric-oxide synthase

major histocompatibility complex

mesenchymal stem cell

prostaglandin E2

T-helper cell

tumor necrosis factor

regulatory T cell.

Work in the Inserm U844 laboratory is supported by the Inserm Institute, the University of Montpellier I and grants from the Agence Nationale de la Recherche (project ANR Physio 2006 Immunostem).

Below are the links to the authors original submitted files for images.

The authors declare that they have no competing interests.

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Immunosuppression by mesenchymal stem cells: mechanisms and …

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The Science of Mesenchymal Stem Cells and Regenerative Medicine

Posted: at 7:44 pm

Arnold Caplan PhD Seven Part Video Series, all presented conveniently here.

June 25, 2013 by jlenner on http://www.CellMedicine.com

(VIDEO Part 1) Professor Arnold Caplan of Case Western Reserve University is widely regarded as The Father of the Mesenchymal Stem Cell. This lecture is a must see for anyone interested in stem cell therapy. In Part 1, Prof. Caplan proposes a new regulatory pathway for approval of cell-based therapies and regenerative medicine called Progressive Approval to replace the current US FDA system that is now in place.

In Part 2, Prof. Caplan discusses the two types of regenerative medicine: tissue engineering and in vivo tissue regeneration, hematapoietic and mesenchymal stem cells. All mesenchymal stem cells are pericytes and have immuno-modulatory and trophic properties.

The Science of Mesenchymal Stem Cells and Regenerative Medicine Arnold Caplan PhD

(VIDEO Part 3)

In part 3, Professor Caplan discusses the science behind mesenchymal stem cells: sources of mesenchymal stem cells (MSCs), because all MSCs are pericytes one can find them in any tissue that has blood vessels, pericytes express markers of MSCs, frequency of pericytes in human tissue, most abundant source of pericytes is adipose (fat) tissue, adipose-derived stem cells, how MSCs are separated from fat, chemistries MSCs from different tissues are not the same, MSCs function at sites of injury, mesenchymal stem cell homing in mice, MSCs dont make fat, they dont make muscle. They come back as pericytes, and not all pericytes are MSCs.

VIDEO The Science of Mesenchymal Stem Cells and Regenerative Medicine Arnold Caplan PhD (Part 4)

In part 4, Prof. Caplan talks about isolating mesenchymal stem cells from bone marrow using specialized; calf serum choosing different assays to prove multipotency osteogenesis, chondrogenesis, adipogenesis; point of care with autologous bone marrow in orthopedic surgery; tissue engineering bone with lineage restricted MSCs; banking bone discarded bone marrow from orthopedic surgeries for future use;

VIDEO The Science of Mesenchymal Stem Cells and Regenerative Medicine Arnold Caplan PhD (Part 5)

In part 5, Prof. Caplan discusses: Mesenchymal stem cells produce huge quantities of bio-molecules, some of which are immunosuppressive; MSCs put up a curtain of molecules around themselves that allows donor (allogeneic) MSCs to be transplanted into a recipient free from immune response; The bio-chemical mechanism of how MSCs shield themselves from host T Cells; Allogeneic hematopoietic stem cell business model; Treatment of graft vs. host disease in children and adults; Treatment of Crohns disease with allogeneic mesenchymal stem cells.

VIDEO The Science of Mesenchymal Stem Cells and Regenerative Medicine Arnold Caplan PhD (Part 6)

In part 6, Prof. Caplan discusses Trophic properties of mesenchymal stem cells; MSCs for heart disease; MSCs homing to heart injury site and also to skin incision site; MSCs limit left ventricular thinning following infarction; Trophic properties of MSCs: anti-apoptotic, anti-fibrotic, anti-scarring, angiogenic, mitotic; phase 1 data for allogeneic MSCs show fewer arrhythmias, prompt heart rate recovery, and improved lung function; autologous adipose tissue-derived stromal vascular fraction for treatment of chronic heart disease; Active mesenchymal stem cell clinical trials around the world; Induction therapy with autologous MSCs in kidney transplants; MSCs can coax neural stem cells to become oligodendrocytes, curing mice with MS using allogeneic human MSCs.

Part 7 In this final segment, Prof. Caplan discusses: Mesenchymal stem cells make anti-bacterial molecules,

In this final segment, Prof. Caplan discusses: Mesenchymal stem cells make anti-bacterial molecules, How retro-orbital injections of human MSCs cure mice with cystic fibrosis infected by pneumonia aeruginosa 70% of the time, The process by which MSCs kill bacteria in the body, Clinical trial for using MSCs to treat sepsis, MSCs are drug stores for sites of injury or inflammation. They are site regulated, multi-drug delivery vehicles, MSC transitions: ostegenic, trophic and immunomodulatory, MSCs are not stromal cells. They are not part of the connective tissue, The name of the MSC has changed. It is a Medicinal Signaling Cell and has nothing whatsoever to do with stem-ness, Cell plasticity, transdifferentiation in the mesengenic process.

June 25, 2013 by jlenner on http://www.CellMedicine.com

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The Science of Mesenchymal Stem Cells and Regenerative Medicine

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Prochymal Adult Human Mesenchymal Stem Cells for Treatment …

Posted: at 7:44 pm

Human mesenchymal stem cells (MSCs), derived from healthy adult volunteer human donors, can be obtained from bone marrow donation and cultured in the laboratory. MSCs have shown the ability to find injured tissue, reduce and control inflammation, and assist in tissue repair.

Prochymal MSCs will be infused into patients with moderate-to-severe Crohn’s disease. Infusions will occur on two separate days, 7-10 days apart. Patients will be monitored for reduced Crohn’s disease symptoms.

High dose (8 million cells per kg of body weight)

Cells in plasmalyte and containing dimethylsulfoxide

Other Name: PROCHYMAL

two infusions, one week apart, each comprising adult human mesenchymal stem cells

Other Name: PROCHYMAL

Low dose: 2 million cells per kg body weight

Cells in plasmalyte and containing dimethylsulfoxide

Other Name: PROCHYMAL

two infusions, one week apart, each comprising adult human mesenchymal stem cells

Other Name: PROCHYMAL

Human mesenchymal stem cells (MSCs), derived from healthy adult volunteer human donors, can be obtained from bone marrow donation and cultured in the laboratory. MSCs have shown the ability to find injured tissue, reduce and control inflammation, and assist in tissue repair.

Prochymal MSCs will be infused into patients with moderate-to-severe Crohn’s disease. Infusions will occur on two separate days, 7-10 days apart. Patients will be monitored for reduced Crohn’s disease symptoms. Patients will receive high or low dose. Study is open label.

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Prochymal Adult Human Mesenchymal Stem Cells for Treatment …

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Mesenchymal Stem Cell Therapy in Multiple System Atrophy …

Posted: July 2, 2016 at 2:46 pm

Describes the nature of a clinical study. Types include:

During the early phases (phases 1 and 2), researchers assess safety, side effects, optimal dosages and risks/benefits. In the later phase (phase 3), researchers study whether the treatment works better than the current standard therapy. They also compare the safety of the new treatment with that of current treatments. Phase 3 trials include large numbers of people to make sure that the result is valid. There are also less common very early (phase 0) and later (phase 4) phases. Phase 0 trials are small trials that help researchers decide if a new agent should be tested in a phase 1 trial. Phase 4 trials look at long-term safety and effectiveness, after a new treatment has been approved and is on the market.

Site IRB

NCT ID: NCT02315027

Sponsor Protocol Number: 12-005950

The purpose of this study is to determine whether mesenchymal stem cells (MSCs) can be safely delivered to the cerebrospinal fluid (CSF) of patients with multiple system atrophy (MSA).

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. If you need assistance understanding the eligibility criteria, please contact the study team.

Inclusion Criteria

Exclusion Criteria

Any of the following conditions will exclude the participant from entering the study:

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Mesenchymal Stem Cell Therapy in Multiple System Atrophy …

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