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      Mesenchymal stem cell therapy in type 2 diabetes mellitus

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          Abstract

          Type 2 diabetes mellitus (T2DM), which is characterized by the combination of relative insulin deficiency and insulin resistance, cannot be reversed with existing therapeutic strategies. Transplantation of insulin-producing cells (IPCs) was once thought to be the most promising strategy for treating diabetes, but the pace from the laboratory to clinical application has been obstructed due to its drawbacks. Mesenchymal stem cells (MSCs) harbor differentiation potential, immunosuppressive properties, and anti-inflammatory effects, and they are considered an ideal candidate cell type for treatment of DM. MSC-related research has demonstrated exciting therapeutic effects in glycemic control both in vivo and in vitro, and these results now have been translated into clinical practice. However, some critical potential problems have emerged from current clinical trials. Multi-center, large-scale, double-blind, and placebo-controlled studies with strict supervision are required before MSC transplantation can become a routine therapeutic approach for T2DM. We briefly review the molecular mechanism of MSC treatment for T2DM as well as the merits and drawbacks identified in current clinical trials.

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          Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure.

          Chutima Talchai, Shouhong Xuan, Hua V. Lin … (2012)
          Diabetes is associated with β cell failure. But it remains unclear whether the latter results from reduced β cell number or function. FoxO1 integrates β cell proliferation with adaptive β cell function. We interrogated the contribution of these two processes to β cell dysfunction, using mice lacking FoxO1 in β cells. FoxO1 ablation caused hyperglycemia with reduced β cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that loss of β cell mass was due to β cell dedifferentiation, not death. Dedifferentiated β cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc. A subset of FoxO1-deficient β cells adopted the α cell fate, resulting in hyperglucagonemia. Strikingly, we identify the same sequence of events as a feature of different models of murine diabetes. We propose that dedifferentiation trumps endocrine cell death in the natural history of β cell failure and suggest that treatment of β cell dysfunction should restore differentiation, rather than promoting β cell replication. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Five-year follow-up after clinical islet transplantation.

            Edmond Ryan, Breay Paty, Peter A. Senior … (2005)
            Islet transplantation can restore endogenous beta-cell function to subjects with type 1 diabetes. Sixty-five patients received an islet transplant in Edmonton as of 1 November 2004. Their mean age was 42.9 +/- 1.2 years, their mean duration of diabetes was 27.1 +/- 1.3 years, and 57% were women. The main indication was problematic hypoglycemia. Forty-four patients completed the islet transplant as defined by insulin independence, and three further patients received >16,000 islet equivalents (IE)/kg but remained on insulin and are deemed complete. Those who became insulin independent received a total of 799,912 +/- 30,220 IE (11,910 +/- 469 IE/kg). Five subjects became insulin independent after one transplant. Fifty-two patients had two transplants, and 11 subjects had three transplants. In the completed patients, 5-year follow-up reveals that the majority ( approximately 80%) have C-peptide present post-islet transplant, but only a minority ( approximately 10%) maintain insulin independence. The median duration of insulin independence was 15 months (interquartile range 6.2-25.5). The HbA(1c) (A1C) level was well controlled in those off insulin (6.4% [6.1-6.7]) and in those back on insulin but C-peptide positive (6.7% [5.9-7.5]) and higher in those who lost all graft function (9.0% [6.7-9.3]) (P < 0.05). Those who resumed insulin therapy did not appear more insulin resistant compared with those off insulin and required half their pretransplant daily dose of insulin but had a lower increment of C-peptide to a standard meal challenge (0.44 +/- 0.06 vs. 0.76 +/- 0.06 nmol/l, P < 0.001). The Hypoglycemic score and lability index both improved significantly posttransplant. In the 128 procedures performed, bleeding occurred in 15 and branch portal vein thrombosis in 5 subjects. Complications of immunosuppressive therapy included mouth ulcers, diarrhea, anemia, and ovarian cysts. Of the 47 completed patients, 4 required retinal laser photocoagulation or vitrectomy and 5 patients with microalbuminuria developed macroproteinuria. The need for multiple antihypertensive medications increased from 6% pretransplant to 42% posttransplant, while the use of statin therapy increased from 23 to 83% posttransplant. There was no change in the neurothesiometer scores pre- versus posttransplant. In conclusion, islet transplantation can relieve glucose instability and problems with hypoglycemia. C-peptide secretion was maintained in the majority of subjects for up to 5 years, although most reverted to using some insulin. The results, though promising, still point to the need for further progress in the availability of transplantable islets, improving islet engraftment, preserving islet function, and reducing toxic immunosuppression.
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              Human gingiva-derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing.

              Qun-Zhou Zhang, Wen-Ru Su, Shi-Hong Shi … (2010)
              Increasing evidence has supported the important role of mesenchymal stem cells (MSCs) in wound healing, however, the underlying mechanism remains unclear. Recently, we have isolated a unique population of MSCs from human gingiva (GMSCs) with similar stem cell-like properties, immunosuppressive, and anti-inflammatory functions as human bone marrow-derived MSCs (BMSCs). We describe here the interplay between GMSCs and macrophages and the potential relevance in skin wound healing. When cocultured with GMSCs, macrophages acquired an anti-inflammatory M2 phenotype characterized by an increased expression of mannose receptor (MR; CD206) and secretory cytokines interleukin (IL)-10 and IL-6, a suppressed production of tumor necrosis factor (TNF)-α, and decreased ability to induce Th-17 cell expansion. In vivo, we demonstrated that systemically infused GMSCs could home to the wound site in a tight spatial interaction with host macrophages, promoted them toward M2 polarization, and significantly enhanced wound repair. Mechanistically, GMSC treatment mitigated local inflammation mediated by a suppressed infiltration of inflammatory cells and production of IL-6 and TNF-α, and an increased expression of IL-10. The GMSC-induced suppression of TNF-α secretion by macrophages appears to correlate with impaired activation of NFκB p50. These findings provide first evidence that GMSCs are capable to elicit M2 polarization of macrophages, which might contribute to a marked acceleration of wound healing.
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                Author and article information

                Contributors
                Li Zang: Zangli301@163.com
                Haojie Hao: haojieh@163.com
                Jiejie Liu: Ljj0558@126.com
                Yijun Li: nmyxylyjy@126.com
                Weidong Han: hanwdrsw69@yahoo.com
                Yiming Mu: +86(10)55499001 , muyiming@301hospital.com.cn
                Journal
                Journal ID (nlm-ta): Diabetol Metab Syndr
                Journal ID (iso-abbrev): Diabetol Metab Syndr
                Title: Diabetology & Metabolic Syndrome
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1758-5996
                Publication date (Electronic): 15 May 2017
                Publication date PMC-release: 15 May 2017
                Publication date Collection: 2017
                Volume: 9
                Electronic Location Identifier: 36
                Affiliations
                [1 ]ISNI 0000 0004 1761 8894, GRID grid.414252.4, Department of Endocrinology, , Chinese PLA General Hospital, ; Beijing, 100853 China
                [2 ]ISNI 0000 0004 1761 8894, GRID grid.414252.4, Department of Molecular Biology, Institute of Basic Medicine, College of Life Science, , Chinese PLA General Hospital, ; Beijing, 100853 China
                Article
                Publisher ID: 233
                DOI: 10.1186/s13098-017-0233-1
                PMC ID: 5433043
                PubMed ID: 28515792
                SO-VID: 12762e7c-4821-4be8-a8f4-c3cdf38004ab
                Copyright © © The Author(s) 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 17 February 2017
                Date accepted : 5 May 2017
                Funding
                Funded by: the National Basic Science and Development Program
                Award ID: 2012CB518103
                Award Recipient :
                Funded by: the 863 Projects of Ministry of Science and Technology of China
                Award ID: 2013AA020105
                Award Recipient :
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: mesenchymal stem cells,type 2 diabetes mellitus,insulin resistance
                Data availability:
                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: mesenchymal stem cells, type 2 diabetes mellitus, insulin resistance

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