Role of mesenchymal stem cell therapy in Crohn's disease

Department of Pediatrics, Children's Mercy Hospital and Clinics, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
Pediatric Research (Impact Factor: 2.31). 04/2012; 71(4 Pt 2):445-51. DOI: 10.1038/pr.2011.56
Source: PubMed


Many trials of mesenchymal stem cells (MSCs) have been published in the past 5-6 y. MSCs inhibit T-cell alloreactivity in vitro by soluble factors and direct cell-to-cell contact. They are safe to infuse in humans with no acute toxicity and no ectopic tissue formation. Promising results of MSC infusion for graft-vs.-host disease and fistulizing Crohn's disease (CD) have been published. Treatment of CD requires a comprehensive treatment approach to maintain symptomatic control, improve health-related quality-of-life measures, and minimize complications from the disease. In this review, we will discuss the results of clinical trials using a novel treatment in the form of MSCs for treatment of CD and related complications. Success of these phase I, II, and III trials have set the stage for usage of this novel treatment for children with CD.

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Available from: Kim L Gandy, Aug 04, 2014
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    • "They have been identified and isolated from multiple tissues, including adipose tissue, umbilical cord, bone marrow, muscle, and fetal liver [4]. Increasing evidence suggests that bone marrowderived mesenchymal stem cells (BMSCs) have therapeutic potential due to their immunosuppressive property in many immunological disorders, including graft-versus-host disease [5], Crohn's disease [6], and the prevention of organ transplantation rejection [7] [8]. Furthermore, many studies have demonstrated that BMSCs play a critical role in injury healing. "
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    ABSTRACT: The recruitment of bone marrow-derived mesenchymal stem cells (BMSCs) to damaged tissues and sites of inflammation is an essential step for clinical therapy. However, the signals regulating the motility of these cells are still not fully understood. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, is known to have a variety of biological effects on various cells. Here, we investigated the roles of S1P and S1P receptors (S1PRs) in migration of human BMSCs. We found that S1P exerted a powerful migratory action on human BMSCs. Moreover, by employing RNA interference technology and pharmacological tools, we demonstrated that S1PR1 and S1PR3 are responsible for S1P-induced migration of human BMSCs. In contrast, S1PR2 mediates the inhibition of migration. Additionally, we explored the downstream signaling pathway of the S1P/S1PRs axis and found that activation of S1PR1 or S1PR3 increased migration of human BMSCs through a G i /extracellular regulated protein kinases 1/2- (ERK1/2-) dependent pathway, whereas activation of S1PR2 decreased migration through the Rho/Rho-associated protein kinase (ROCK) pathway. In conclusion, we reveal that the S1P/S1PRs signaling axis regulates the migration of human BMSCs via a dual-directional mechanism. Thus, selective modulation of S1PR’s activity on human BMSCs may provide an effective approach to immunotherapy or tissue regeneration.
    Mediators of Inflammation 07/2014; 2014(4):565369. DOI:10.1155/2014/565369 · 3.24 Impact Factor
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    • "The above mentioned and/or other mechanisms can change the inflammatory environment to immune tolerant. It looks suitable the use of the immunosuppressive activity of MSC to the treatment of autoimmune diseases [14] [15] as well as of graft-versus-host-disease (GVHD), an important complication after allogeneic hematopoietic cells transplantation [16]. GVHD is "
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    ABSTRACT: Mesenchymal stromal cells (MSC) are fibroblast-like cells present in different types of tissues. Their immunomodulatory potential represents a promising method for post-transplant immunotherapy in the treatment of GVHD (graft-versus-host disease) with suboptimal response to standard immunosuppression. In this study we tested influence of 1–8 month-long cryopreservation on ability of MSC to suppress activation of non-specifically stimulated lymphocytes. We did not observe any changes in proliferation capacity of MSC after thawing. Lymphocytes metabolic activity was inhibited by 30% and number of dividing cells was three times smaller in the presence of MSC. Two activation markers were studied (CD25 and CD69) to confirm preservation of functional cell integrity. Expression of CD25 antigen on CD3+CD4+ and CD3+CD4− cells was decreased in all co-cultivated samples. Level of CD69 expression on CD3+CD4+ cells was lower in samples with added MSC (10–15% on day +2) but without reaching statistical significance. The lower expression (approximately 5%) was observed also on CD4-cells. The study confirms the preservation of immunomodulatory properties of cryopreserved and re-expanded MSC. Aliquots with cryopreserved cells can represent an optimal source for a quick preparation of MSC cell product with the possibility to apply the same cells repeatedly.
    Biologicals 05/2014; 42(3). DOI:10.1016/j.biologicals.2014.01.003 · 1.21 Impact Factor
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    • "Mesenchymal stromal cells (MSCs) have been shown to have therapeutic potential in many immunological disorders including graft-versus-host disease (8), Crohn's disease (9) and rheumatoid arthritis (10). An increasing number of in vitro studies have shown that MSCs have the capability to affect both innate and adaptive immune response. "
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    ABSTRACT: Mesenchymal stromal cells (MSC) are shown to have a great therapeutic potential in many immunological disorders. Currently the therapeutic effect of MSCs is considered to be mediated via paracrine interactions with immune cells. Umbilical cord blood is an attractive but still less studied source of MSCs. We investigated the production of extracellular membrane vesicles (MVs) from human umbilical cord blood derived MSCs (hUCBMSC) in the presence (MVstim) or absence (MVctrl) of inflammatory stimulus. hUCBMSCs were cultured in serum free media with or without IFN-γ and MVs were collected from conditioned media by ultracentrifugation. The protein content of MVs were analyzed by mass spectrometry. Hypoxia induced acute kidney injury rat model was used to analyze the in vivo therapeutic potential of MVs and T-cell proliferation and induction of regulatory T cells were analyzed by co-culture assays. Both MVstim and MVctrl showed similar T-cell modulation activity in vitro, but only MVctrls were able to protect rat kidneys from reperfusion injury in vivo. To clarify this difference in functionality we made a comparative mass spectrometric analysis of the MV protein contents. The IFN-γ stimulation induced dramatic changes in the protein content of the MVs. Complement factors (C3, C4A, C5) and lipid binding proteins (i.e apolipoproteins) were only found in the MVctrls, whereas the MVstim contained tetraspanins (CD9, CD63, CD81) and more complete proteasome complex accompanied with MHCI. We further discovered that differently produced MV pools contained specific Rab proteins suggesting that same cells, depending on external signals, produce vesicles originating from different intracellular locations. We demonstrate by both in vitro and in vivo models accompanied with a detailed analysis of molecular characteristics that inflammatory conditioning of MSCs influence on the protein content and functional properties of MVs revealing the complexity of the MSC paracrine regulation.
    12/2013; 2. DOI:10.3402/jev.v2i0.21927
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