Mesenchymal stem cells and differentiated insulin producing cells are new horizons for pancreatic regeneration in type I diabetes mellitus

Domouky, Ayat M.; Hegab, Ashraf S.; Al-Shahat, Amal; Raafat, Nermin

doi:10.1016/j.biocel.2017.03.018

Cited by 33 publications

(26 citation statements)

References 42 publications

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“…To develop a GDM model, we treated the pregnant rats on gestational day 12 with STZ as previously described 24, 25, 35, 36. As shown in Figure 1, treatment with STZ showed a time-dependent increase in blood glucose level and constantly remained higher blood glucose level throughout period of pregnancy (Figure 1A), which was associated a decrease in maternal body weight gain (Figure 1B).…”

Section: Resultsmentioning

confidence: 96%

Epigenetic Down-Regulation of Sirt 1 via DNA Methylation and Oxidative Stress Signaling Contributes to the Gestational Diabetes Mellitus-Induced Fetal Programming of Heart Ischemia-Sensitive Phenotype in Late Life

Chen¹,

Gong²,

Zhang³

et al. 2019

Int. J. Biol. Sci.

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Rationale: The incidence of gestational diabetes mellitus (GDM) is increasing worldwide. However, whether and how GDM exposure induces fetal programming of adult cardiac dysfunctional phenotype, especially the underlying epigenetic molecular mechanisms and theranostics remain unclear. To address this problem, we developed a late GDM rat model. Methods: Pregnant rats were made diabetic on day 12 of gestation by streptozotocin (STZ). Experiments were conducted in 6 weeks old offspring. Results: There were significant increases in ischemia-induced cardiac infarction and gender-dependent left ventricular (LV) dysfunction in male offspring in GDM group as compared to controls. Exposure to GDM enhanced ROS level and caused a global DNA methylation in offspring cardiomyocytes. GDM attenuated cardiac Sirt 1 protein and p-Akt/Akt levels, but enhanced autophagy-related proteins expression (Atg 5 and LC3 II/LC3 I) as compared to controls. Ex-vivo treatment of DNA methylation inhibitor, 5-Aza directly inhibited Dnmt3A and enhanced Sirt 1 protein expression in fetal hearts. Furthermore, treatment with antioxidant, N-acetyl-cysteine (NAC) in offspring reversed GDM-mediated DNA hypermethylation, Sirt1 repression and autophagy-related gene protein overexpression in the hearts, and rescued GDM-induced deterioration in heart ischemic injury and LV dysfunction. Conclusion: Our data indicated that exposure to GDM induced offspring cardiac oxidative stress and DNA hypermethylation, resulting in an epigenetic down-regulation of Sirt1 gene and aberrant development of heart ischemia-sensitive phenotype, which suggests that Sirt 1-mediated signaling is the potential therapeutic target for the heart ischemic disease in offspring.

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Section: Resultsmentioning

confidence: 96%

Epigenetic Down-Regulation of Sirt 1 via DNA Methylation and Oxidative Stress Signaling Contributes to the Gestational Diabetes Mellitus-Induced Fetal Programming of Heart Ischemia-Sensitive Phenotype in Late Life

Chen¹,

Gong²,

Zhang³

et al. 2019

Int. J. Biol. Sci.

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“…The first possibility may be that the number of transplanted IPCs is not enough for the donor's body size. We transplanted 1.5 × 10 6 AT-MSCs according to a previous study that showed transplantation of IPCs differentiated from human BM-MSCs into STZ-induced diabetic rats [ 43 ]. The study demonstrated that intraperitoneal transplantation of 1.5 × 10 6 BM-MSCs that differentiated into IPCs into diabetic rats led to the improvement of the hyperglycemic states.…”

Section: Discussionmentioning

confidence: 99%

Generation of Insulin-Producing Cells from Canine Adipose Tissue-Derived Mesenchymal Stem Cells

Teshima

Okamoto

Dairaku

et al. 2020

Stem Cells International

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The potential of mesenchymal stem cells (MSCs) to differentiate into nonmesodermal cells such as pancreatic beta cells has been reported. New cell-based therapy using MSCs for diabetes mellitus is anticipated as an alternative treatment option to insulin injection or islet transplantation in both human and veterinary medicine. Several protocols were reported for differentiation of MSCs into insulin-producing cells (IPCs), but no studies have reported IPCs generated from canine MSCs. The purpose of this study was to generate IPCs from canine adipose tissue-derived MSCs (AT-MSCs) in vitro and to investigate the effects of IPC transplantation on diabetic mice in vivo. Culturing AT-MSCs with the differentiation protocol under a two-dimensional culture system did not produce IPCs. However, spheroid-like small clusters consisting of canine AT-MSCs and human recombinant peptide μ-pieces developed under a three-dimensional (3D) culture system were successfully differentiated into IPCs. The generated IPCs under 3D culture condition were stained with dithizone and anti-insulin antibody. Canine IPCs also showed gene expression typical for pancreatic beta cells and increased insulin secretion in response to glucose stimulation. The blood glucose levels in streptozotocin-induced diabetic mice were decreased after injection with the supernatant of canine IPCs, but the hyperglycemic states of diabetic mice were not improved after transplanting IPCs subcutaneously or intramesenterically. The histological examination showed that the transplanted small clusters of IPCs were successfully engrafted to the mice and included cells positive for insulin by immunofluorescence. Several factors, such as the transplanted cell number, the origin of AT-MSCs, and the differentiation protocol, were considered potential reasons for the inability to improve the hyperglycemic state after IPC transplantation. These findings suggest that canine AT-MSCs can be differentiated into IPCs under a 3D culture system and IPC transplantation may be a new treatment option for dogs with diabetes mellitus.

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“…In our experiment, we chose gene therapy instead of stem cell differentiation for the insulin supply. It has been reported that embryonic stem cells [27], pancreatic progenitor cells [28], and MSCs [29] can be differentiated into pancreatic β cells or islet precursor cells. However, the differentiation efficiency and maturity of the resulting cells remained a challenge.…”

Section: Discussionmentioning

confidence: 99%

Adipocyte-derived stem cell-based gene therapy upon adipogenic differentiation on microcarriers attenuates type 1 diabetes in mice

Fang

Zhai

et al. 2019

Stem Cell Res Ther

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BackgroundInsulin replenishment is critical for patients with type 1 diabetes; however, current treatments such as pancreatic islet transplantation and insulin injection are not ideal. In addition to stem cell or gene therapy alone, stem cell combined with gene therapy may provide a new route for insulin replenishment, which could avoid an autoimmune reaction against differentiated β cells or systematic viral vector injection.MethodsIn this study, human adipocyte-derived stem cells (ADSCs) were transducted with lentiviral vectors expressing a furin-cleavable insulin gene. The expression levels of insulin were measured before and after adipogenic differentiation in the presence or absence of an adipocyte-specific promoter AP2. In vitro proliferation and in vivo survival of cells were examined on cytodex and cytopore microcarriers. The effect of ADSC-based gene therapy upon adipogenic differentiation on microcarriers was evaluated in the streptozotocin-induced type 1 diabetic mouse model.ResultsWe found that differentiation of ADSCs into adipocytes increased insulin expression under the EF1 promoter, while adipocyte-specific AP2 promoter further increased insulin expression upon differentiation. The microcarriers supported cell attachment and proliferation during in vitro culture and facilitate cell survival after transplantation. Functional cells on the cytopore 1 microcarrier formed tissue-like structures and alleviated hyperglycemia in the type 1 diabetic mice after subcutaneous injection.ConclusionsOur results indicated that differentiation of ADSC and tissue-specific promotors may enhance the expression of therapeutic genes. The use of microcarriers may facilitate cell survival after transplantation and hold potential for long-term cell therapy.

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Mesenchymal stem cells and differentiated insulin producing cells are new horizons for pancreatic regeneration in type I diabetes mellitus

Cited by 33 publications

References 42 publications

Epigenetic Down-Regulation of Sirt 1 via DNA Methylation and Oxidative Stress Signaling Contributes to the Gestational Diabetes Mellitus-Induced Fetal Programming of Heart Ischemia-Sensitive Phenotype in Late Life

Epigenetic Down-Regulation of Sirt 1 via DNA Methylation and Oxidative Stress Signaling Contributes to the Gestational Diabetes Mellitus-Induced Fetal Programming of Heart Ischemia-Sensitive Phenotype in Late Life

Generation of Insulin-Producing Cells from Canine Adipose Tissue-Derived Mesenchymal Stem Cells

Adipocyte-derived stem cell-based gene therapy upon adipogenic differentiation on microcarriers attenuates type 1 diabetes in mice

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