New Strategies for Overcoming Limitations of Mesenchymal Stem Cell-Based Immune Modulation

Kim, Nayoun; Cho, Seok Goo

doi:10.15283/ijsc.2015.8.1.54

Cited by 116 publications

(87 citation statements)

References 124 publications

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“…2A), and IMT504 treatment, or saline as control, was commenced (day 1). Blood glucose increased progressively in STZ-saline mice during 10 wk of evaluation, whereas it decreased significantly in STZ-IMT504 mice (repeated-measures 2-way ANOVA, interaction P Ͻ 0.001, STZ-IMT504 different from STZ-saline on days 6,11,21,26,29,32,36,41,46,53, and 66, P Ͻ 0.01 or less; Fig. 2A).…”

Section: First Experimental Design: Long-term Effect Of Imt504 In Mldmentioning

confidence: 96%

“…of doses : 20). Glycemia was measured in tail blood samples in nonfasted conditions on days 1,6,11,17,21,26,29,32,36,41,46,53, and 66 at 11-12 AM (last IMT504 injection on day 40). Intraperitoneal glucose tolerance tests (IPGTT) were performed on day 60.…”

Section: First Experimental Design: Long-term Effects Of Imt504 In DImentioning

confidence: 99%

“…Furthermore, mesenchymal stem cells (MSCs) have been assayed as cell-based treatments for inflammatory disorders, including T1D (27), since they promote immunomodulation and regeneration (47). However, their translation into clinic has remained problematic (26). An exciting alternative to MSC transplantation, but one related to it, consists in using therapeutic agents that can stimulate endogenous MSC expansion in the affected being.…”

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confidence: 99%

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Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes

Bianchi

Hernado-Insúa

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Ϫ1 ·day Ϫ1 ip for 5 consecutive days). We determined blood glucose, glucose tolerance, serum insulin, islet morphology, islet infiltration, serum cytokines, progenitor cell markers, immunomodulatory proteins, proliferation, apoptosis, and islet gene expression. IMT504 reduced glycemia, induced ␤-cell recovery, and impaired islet infiltration. IMT504 induced early blood glucose decrease and infiltration inhibition, increased ␤-cell proliferation and decreased apoptosis, increased islet indoleamine 2,3-dioxygenase (IDO) expression, and increased serum tumor necrosis factor and interleukin-6 (IL-6). IMT504 affected islet gene expression; preproinsulin-2, proglucagon, somatostatin, nestin, regenerating gene-1, and C-X-C motif ligand-1 cytokine (Cxcl1) increased in islets from diabetic mice and were decreased by IMT504. IMT504 downregulated platelet endothelial cell adhesion molecule-1 (Pecam1) in islets from control and diabetic mice, whereas it increased regenerating gene-2 (Reg2) in islets of diabetic mice. The IMT504-induced increase in IL-6 and islet IDO expression and decreased islet Pecam1 and Cxcl1 mRNA expression could participate in keeping leukocyte infiltration at bay, whereas upregulation of Reg2 may mediate ␤-cell regeneration. We conclude that IMT504 effectively reversed immunodependent diabetes in mice. Corroboration of these effects in a model of autoimmune diabetes more similar to human T1D could provide promising results for the treatment of this disease.

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Section: First Experimental Design: Long-term Effect Of Imt504 In Mldmentioning

confidence: 96%

Section: First Experimental Design: Long-term Effects Of Imt504 In DImentioning

confidence: 99%

mentioning

confidence: 99%

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Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes

Bianchi

Hernado-Insúa

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…MSCs can differentiate into various types of cell including osteoblasts, chondrocytes, adipocytes, neurons, and cardiomyocytes (Toma et al, 2002;Chuah et al, 2015;Pipino and Pandolfi, 2015;Zhuang et al, 2015) and exhibit beneficial effects such as angiogenesis and immune regulation (Castro-Manrreza and Montesinos, 2015;Kim and Cho, 2015). Potential functions of MSCs vary depending on the source and different experimental conditions, and MSCs can be used in clinical applications to treat different kinds of disease (Garcia-Olmo et al, 2009;Cho et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Enhancement of angiogenic effects by hypoxia‐preconditioned human umbilical cord‐derived mesenchymal stem cells in a mouse model of hindlimb ischemia

Han

Kim

et al. 2015

Cell Biology International

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It has been studied that mesenchymal stem cells (MSCs) have the capability to promote angiogenesis. Furthermore, there is strong evidence that hypoxic conditions can enhance angiogenesis and immune modulation mediated by MSCs, a notion that has been applied in many fields of clinical application. In the present study, we compared the efficacy of hypoxia preconditioned human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and normoxia conditioned hUC-MSCs for the treatment of ischemic injury in hindlimbs of an immunodeficient mouse model. Expression of negative markers for MSC such as CD31, CD34, and CD45 or positive markers such as CD44, CD73, CD90, and CD105 was not significantly changed in hypoxia preconditioned hUC-MSCs compared with hUC-MSCs cultured in normoxic condition. Expression of angiogenesis-related genes such as COX-2, VEGF, Tie-2, and TGF-β1 was increased compared with hUC-MSCs cultured in normoxic conditions. In the in vivo model, CD31 expression as a marker of angiogenesis was significantly increased in the ischemic limbs at 1 month after injection with hypoxic hUC-MSCs. Angiogenesis-related genes such as Ang-1, COX-1, PIGF, and MCP-1 were significantly upregulated in the muscle of ischemic hindlimbs treated with hypoxic hUC-MSCs than normoxic hUC-MSCs. Expression of proinflammatory genes such as IL-1, and IL-20 was reduced, whereas TGF-β1, which has an anti-inflammatory effect, was strongly increased. In conclusion, hypoxic culture conditions could induce expression of angiogenesis related genes in hUC-MSCs, and hypoxia preconditioned hUC-MSCs showed enhancing effects by inducing angiogenesis and low inflammatory immune response compared with normoxic hUC-MSCs in the ischemia injured hindlimb of immunodeficient mice.

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“…As far as it concerns VCA, there is only a small body of evidence for the modulatory effects of MSCs. Recent reports point out to a beneficial immunomodulatory effect of both BMMSCs and ASCs on the survival rate of rat hind limbs [30]). …”

Section: Modulation Of Immune Responsementioning

confidence: 99%

Premise and promise of mesenchymal stem cell-based therapies in clinical vascularized composite allotransplantation

Schweizer

Gorantla

Plock

2015

Current Opinion in Organ Transplantation

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PURPOSE OF REVIEW Over the past decade, clinical vascularized composite allotransplantation (VCA) has enabled functional and quality of life restoration in a wide range of indications secondary to devastating tissue loss. However, the spectre of toxicity and long-term complications of chronic immunosuppression has curtailed the momentum of VCA. This study summarizes the literature evidence behind successful mesenchymal stem cell (MSC)-based cell therapies highlighting their multipronged immunomodulatory, restorative and regenerative characteristics with special emphasis towards VCA applications. RECENT FINDINGS Experimental and clinical studies in solid organs and VCA have confirmed that MSCs facilitate immunosuppression-free allograft survival or tolerance, stimulate peripheral nerve regeneration, attenuate ischaemia-reperfusion injury, and improve tissue healing after surgery. It has been hypothesized that MSC-induced long-term operational tolerance in experimental VCA is mediated by induction of mixed donor-specific chimerism and regulatory T-cell mechanisms. All these characteristics of MSCs could thus help expand the scope and clinical feasibility of VCA. SUMMARY Cellular therapies, especially those focusing on MSCs, are emerging in solid organ transplantation including VCA. Although some clinical trials have begun to assess the effects of MSCs in solid organ transplantation, much scientific domain remains uncharted, especially for VCA. Purpose of review Over the past decade, clinical vascularized composite allotransplantation (VCA) has enabled functional and quality of life restoration in a wide range of indications secondary to devastating tissue loss. However, the spectre of toxicity and long-term complications of chronic immunosuppression has curtailed the momentum of VCA. This study summarizes the literature evidence behind successful mesenchymal stem cell (MSC)-based cell therapies highlighting their multipronged immunomodulatory, restorative and regenerative characteristics with special emphasis towards VCA applications. Recent findingsExperimental and clinical studies in solid organs and VCA have confirmed that MSCs facilitate immunosuppression-free allograft survival or tolerance, stimulate peripheral nerve regeneration, attenuate ischaemia-reperfusion injury, and improve tissue healing after surgery. It has been hypothesized that MSCinduced long-term operational tolerance in experimental VCA is mediated by induction of mixed donorspecific chimerism and regulatory T-cell mechanisms. All these characteristics of MSCs could thus help expand the scope and clinical feasibility of VCA. SummaryCellular therapies, especially those focusing on MSCs, are emerging in solid organ transplantation including VCA. Although some clinical trials have begun to assess the effects of MSCs in solid organ transplantation, much scientific domain remains uncharted, especially for VCA.

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New Strategies for Overcoming Limitations of Mesenchymal Stem Cell-Based Immune Modulation

Cited by 116 publications

References 124 publications

Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes

Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes

Enhancement of angiogenic effects by hypoxia‐preconditioned human umbilical cord‐derived mesenchymal stem cells in a mouse model of hindlimb ischemia

Premise and promise of mesenchymal stem cell-based therapies in clinical vascularized composite allotransplantation

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