Human bone marrow mesenchymal stem cells differentiate into insulin-producing cells upon microenvironmental manipulation in vitro

Department of Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang province 310009, PR China.
Differentiation (Impact Factor: 3.44). 07/2009; 77(5):483-91. DOI: 10.1016/j.diff.2009.01.001
Source: PubMed


It was recently reported that pluripotent mesenchymal stem cells (MSCs) in rodent bone marrow (BM) have the capacity to generate insulin-producing cells (IPCs) in vitro. However, little is known about this capacity in human BM-MSCs. We developed a nongenetic method to induce human BM-MSCs to transdifferentiate into IPCs both phenotypically and functionally. BM-MSCs from 12 human donors were sequentially cultured in specially defined conditions. Their differentiation extent toward beta-cell phenotype was evaluated systemically. Specifically, after induction human BM-MSCs formed spheroid islet-like clusters containing IPCs, which was further confirmed by dithizone (DTZ) staining and electron microscopy. These IPCs expressed multiple genes related to the development or function of pancreatic beta cells (including NKX6.1, ISL-1, Beta2/Neurod, Glut2, Pax6, nestin, PDX-1, ngn3, insulin and glucagon). The coexpression of insulin and c-peptide was observed in IPCs by immunofluorescence. Moreover, they were able to release insulin in a glucose-dependent manner and ameliorate the diabetic conditions of streptozotocin (STZ)-treated nude mice. These results indicate that human BM-MSCs might be an available candidate to overcome limitations of islet transplantation.

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    • "Thus, the reduced SYT-7 levels in T-IPCs compared with those in A-IPCs can cause decreased insulin secretion from differentiated IPCs. Although several methods for differentiating MSCs into IPCs have been reported previously (Karaoz et al., 2013; Xie et al., 2009; Kim et al., 2012b, 2012a; Moshtagh et al., 2013; Jafarian et al., 2014), there has been no direct comparison among them. We compared the efficacies of the β-mercaptoethanol method (Chen et al., 2004; Moshtagh et al., 2013) and the ITS method (Kanafi et al., 2013; Kim et al., 2012a; Jafarian et al., 2014) and revealed the superior efficacy of the ITS method in terms of higher pancreatic marker gene expression and GSIS. "
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    ABSTRACT: Tonsil-derived (T-) mesenchymal stem cells (MSCs) display mutilineage differentiation potential and self-renewal capacity and have potential as a banking source. Diabetes mellitus is a prevalent disease in modern society, and the transplantation of pancreatic progenitor cells or various stem cell-derived insulin-secreting cells has been suggested as a novel therapy for diabetes. The potential of T-MSCs to trans-differentiate into pancreatic progenitor cells or insulin-secreting cells has not yet been investigated. We examined the potential of human T-MSCs to trans-differentiate into pancreatic islet cells using two different methods based on β-mercaptoethanol and insulin-transferin-selenium, respectively. First, we compared the efficacy of the two methods for inducing differentiation into insulin-producing cells. We demonstrated that the insulin-transferin-selenium method is more efficient for inducing differentiation into insulin-secreting cells regardless of the source of the MSCs. Second, we compared the differentiation potential of two different MSC types: T-MSCs and adipose-derived MSCs (A-MSCs). T-MSCs had a differentiation capacity similar to that of A-MSCs and were capable of secreting insulin in response to glucose concentration. Islet-like clusters differentiated from T-MSCs had lower synaptotagmin-3, -5, -7, and -8 levels, and consequently lower secreted insulin levels than cells differentiated from A-MSCs. These results imply that T-MSCs can differentiate into functional pancreatic islet-like cells and could provide a novel, alternative cell therapy for diabetes mellitus.
    Differentiation 09/2015; DOI:10.1016/j.diff.2015.08.001 · 3.44 Impact Factor
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    • "INSULIN transcript was evenly expressed in all DPSC lines differentiated into pancreatic cells, but both of PDX-1 and GLUT-2 transcripts have revealed to be expressed with slight variations, depending on DPSCs cell types used. It has been demonstrated by previous studies that the expression of pancreas-specific transcripts are observed in differentiated bone-marrow-derived MSCs with spheroid cluster (Xie et al. 2009; Kim et al. 2012; Karaoz et al. 2013; Moshtagh et al. 2013). However, some of these spheroid clusters were not stained with DTZ cytochemical solution and also these DPSC lines possess a relatively poor capacity to differentiate into pancreatic cells when compared to that of neuronal differentiation. "
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    ABSTRACT: Mesenchymal stem cells (MSCs) possess the ability to differentiate into non-mesodermal lineage, and examining their multi-potency will be beneficial for application in regenerative medicine. The present study investigated the differentiation capacity into neuronal cells of ectodermal lineage and pancreatic cells of endodermal lineage in each of MSC lines isolated from three samples of human dental papilla tissues (DPSCs). Isolated DPSC lines expressed CD13, CD44, CD73, CD90 and CD105 cell surface markers, and OCT-4, NANOG and SOX-2 transcription factors. Further, all DPSC lines differentiated into osteocytes, adipocytes and chondrocytes of mesodermal lineage, whereas telomerase activity was at a low level in all isolated DPSC lines. Following induction into neuronal cells of ectodermal lineage, the neuron-like morphological alterations and expression of neuro-filament M by immunocytochemical staining was observed in all types of DPSCs, and expression of neuronal cell-specific transcripts, NSE, MAP-2, and NESTIN was further confirmed by reverse transcription-polymerase chain reaction (RT-PCR). Moreover, following induction into pancreatic cells of endodermal lineage, all DPSC lines exhibited morphological alterations with DTZ-positive spheroid clusters, and expression of pancreatic cell-specific transcripts, INSULIN, PDX-1, and GLUT-2, was positively detected by RT-PCR. However, some of these clusters were negatively reacted with DTZ staining. The present results demonstrated that DPSCs exhibit differentiation capacity into neuronal and pancreatic cells of non-mesodermal lineage, and DPSCs could be an alternative source of MSCs for clinical applications.
    Animal cells and systems the official publication of the Zoological Society of Korea 09/2015; 19(5). DOI:10.1080/19768354.2015.1087430 · 0.44 Impact Factor
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    • "Koblas and colleagues, classify them in two concomitant groups of cells, CD133- positive pancreatic cells which contain endocrine progenitors capable of expressing neurogenin-3 and, cells expressing human telomerase, ABCG2, Oct-3/4, Nanog , and Rex-1 which carry markers of pluripotentency (Koblas et al., 2008). Eventually results showed that these cells were highly proficient insulin producing cells in a glucose-dependent modus that led to amelioration of diabetic disorders in streptozotocin-treated nude mice (Xie et al., 2009). Of note, data from different lines of studies seem to confirm the role of in vivo hyperglycemia as a crucial element for MSCs "

    09/2015; 2(8). DOI:10.7603/s40730-015-0019-8
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