Autologous bone marrow-derived rat mesenchymal stem cells promote PDX-1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia

Boumaza, Imene; Srinivasan, Suganya; Witt, William T.; Feghali‐Bostwick, Carol; Dai, Yifan; Garcı́a-Ocaña, Adolfo; Feili-Hariri, Maryam

doi:10.1016/j.jaut.2008.10.004

Cited by 147 publications

(133 citation statements)

References 57 publications

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“…Therefore, an amplifying loop that mediates and propagates immunomodulation while inhibiting the maturation of inflammatory DCs can be envisaged [19]. Although data regarding the effects on beta cell function and survival remain controversial [45,46], IL-6 may also stimulate beta cell repair. Thus, in DC-MSC combination therapy, multiple layers of tolerance could be formed involving regulatory DCs, T cells and even B cells [47] that may act and accumulate in relevant tissue.…”

Section: Discussionmentioning

confidence: 99%

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

et al. 2015

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Aims/hypothesis Mesenchymal stem cells (MSCs) can exert an immunosuppressive effect on any component of the immune system, including dendritic cells (DCs), by direct contact, the release of soluble markers and extracellular vesicles (EVs). We evaluated whether MSCs and MSC-derived EVs have an immunomodulatory effect on monocyte-derived DCs in type 1 diabetes. Methods Bone marrow derived MSCs were characterised and EVs were obtained by ultracentrifugation. DCs were differentiated from CD14 + cells, obtained from nine type 1 diabetic patients at disease onset, pulsed with antigen GAD65 and cultured with MSCs or EVs. Levels of DC maturation and activation markers were evaluated by flow cytometry. GAD65-pulsed DCs and autologous CD14− cell were cocultured and IFN-γ enzyme-linked immunosorbent spot responses were assayed. Secreted cytokine levels were measured and Th17 and regulatory T cells were analysed.Results MSC-and EV-conditioned DCs acquired an immature phenotype with reduced levels of activation markers and increased IL-10 and IL-6 production. Conditioned DC plus T cell co-cultures showed significantly decreased IFN-γ spots and secretion levels. Moreover, higher levels of TGF-β, IL-10 and IL-6 were detected compared with unconditioned DC plus T cell co-cultures. Conditioned DCs decreased Th17 cell numbers and IL-17 levels, and increased FOXP3 + regulatory T cell numbers. EVs were internalised by DCs and EV-conditioned DCs exhibited a similar effect. Conclusions/interpretation In type 1 diabetes, MSCs induce immature IL-10-secreting DCs in vitro, thus potentially intercepting the priming and amplification of autoreactive T cells in tissue inflammation. These DCs can contribute to the inhibition of inflammatory T cell responses to islet antigens and the promotion of the anti-inflammatory, regulatory responses exerted by MSCs.

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Section: Discussionmentioning

confidence: 99%

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

et al. 2015

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“…Third, the therapeutic efficacy of the two subsets attributes clear advantage of the Fr25lin − cells in stabilization of glucose levels through sustained increase in insulin levels. In contrast, R/O progenitors and whole BMC grafts share limited capacity to elevate insulin levels, corroborating the partial and transient reduction in blood glucose levels mediated by hematopoietic progenitors (6,7,14,18,27,39,41,47,56).…”

Section: Discussionmentioning

confidence: 65%

Two Distinct Mechanisms Mediate the Involvement of Bone Marrow Cells in Islet Remodeling: Neogenesis of Insulin-Producing Cells and Support of Islet Recovery

et al. 2015

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We have recently reported that small-sized bone marrow cells (BMCs) isolated by counterflow centrifugal elutriation and depleted of lineage markers (Fr25lin − ) have the capacity to differentiate and contribute to regeneration of injured islets. In this study, we assess some of the characteristics of these cells compared to elutriated hematopoietic progenitors (R/O) and whole BMCs in a murine model of streptozotocin-induced chemical diabetes. The GFP bright CD45+ progeny of whole BMCs and R/O progenitors progressively infiltrate the pancreas with evolution of donor chimerism; are found at islet perimeter, vascular, and ductal walls; and have a modest impact on islet recovery from injury. In contrast, Fr25lin− cells incorporate in the islets, convert to GFP dim CD45 − PDX-1 + phenotypes, produce proinsulin, and secrete insulin with significant contribution to stabilization of glucose homeostasis. The elutriated Fr25lin − cells express low levels of CD45 and are negative for SCA-1 and c-kit, as removal of cells expressing these markers did not impair conversion to produce insulin. BMCs mediate two synergistic mechanisms that contribute to islet recovery from injury: support of islet remodeling by hematopoietic cells and neogenesis of insulin-producing cells from stem cells.

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“…Therefore, it is critical to use healthy MSCs for cell-based immune therapies. MSCs have also shown efficacy and safety in several clinical trials for myocardial infarction, acute lung injury, chronic obstructive pulmonary disease (COPD), diabetes, and Crohn's disease, a painful inflammatory disease in the bowels and gastrointestinal tract (Boumaza et al, 2009;Hare et al, 2009;Ciccocioppo et al, 2011;Matthay et al, 2010;Mannon, 2011;Mabed and Shahin, 2012). Recently, Osiris Therapeutics, Inc. (Columbia, MD, USA) has received market authorization in Canada to market the first undifferentiated stem cell product, Prochymal ® , an intravenously administered formulation of MSCs derived from human bone marrow of healthy adults, for the management of acute GVHD in children who are unresponsive to steroids (Prasad et al, 2011;Pollack, 2012).…”

Section: Mscs Target Lymphocytesmentioning

confidence: 99%

Interplay between Mesenchymal Stem Cells and Lymphocytes

2012

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In addition to their potential for replacing damaged and diseased tissues by differentiating into tissuespecific cells, mesenchymal stem cells (MSCs) have been found to interact closely with immune cells, such as lymphocytes. In this review, we will discuss current research regarding the immunomodulatory properties of MSCs and the effects of lymphocytes on MSCs. We will suggest how these findings could be translated to potential clinical treatment. MSCs can regulate immune response by inducing activated T-cell apoptosis through the FAS ligand (FASL)/FAS-mediated death pathway via cell-cell contact, leading to up-regulation of regulatory T-cells (Tregs), which ultimately results in immune tolerance. Conversely, lymphocytes can impair survival and osteogenic differentiation of implanted MSCs by secreting the pro-inflammatory cytokines IFN-γ and TNF-α and/or through the FASL/FAS-mediated death pathway, thereby negatively affecting MSC-mediated tissue regeneration. One novel strategy to improve MSC-based tissue engineering involves the reduction of IFN-γ and TNF-α concentration by systemic infusion of Tregs or local application of aspirin. Further understanding of the mechanisms underlying the interplay between lymphocytes and MSCs may be helpful in the development of promising approaches to improve cell-based regenerative medicine and immune therapies.

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Autologous bone marrow-derived rat mesenchymal stem cells promote PDX-1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia

Cited by 147 publications

References 57 publications

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

Two Distinct Mechanisms Mediate the Involvement of Bone Marrow Cells in Islet Remodeling: Neogenesis of Insulin-Producing Cells and Support of Islet Recovery

Interplay between Mesenchymal Stem Cells and Lymphocytes

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