Human Bone Marrow Mesenchymal Stem Cells Can Express Insulin and Key Transcription Factors of the Endocrine Pancreas Developmental Pathway upon Genetic and/or Microenvironmental Manipulation In Vitro

Abstract

Multipotential stem cells can be selected from the bone marrow by plastic adhesion, expanded, and cultured. They are able to differentiate not only into multiple cell types, including cartilage, bone, adipose and fibrous tissues, and myelosupportive stroma, but also into mesodermal (endothelium), neuroectodermal, or endodermal (hepatocytes) lineages. Our goal was to characterize the multipotential capacities of human mesenchymal stem cells (hMSCs) and to evaluate their ability to differentiate into insulin-secreting cells in vitro. hMSCs were obtained from healthy donors, selected by plastic adhesion, and phenotyped by fluorescence-activated cell sorter and reverse transcription-polymerase chain reaction analysis before and after infection with adenoviruses coding for mouse IPF1, HLXB9, and FOXA2 transcription factors involved early in the endocrine developmental pathway. We found that native hMSCs have a pluripotent phenotype (OCT4 expression and high telomere length) and constitutively express NKX6-1 at a low level but lack all other transcription factors implicated in beta-cell differentiation. In all hMSCs, we detected mRNA of cytokeratin 18 and 19, epithelial markers present in pancreatic ductal cells, whereas proconvertase 1/3 mRNA expression was detected only in some hMSCs. Ectopic expression of IPF1, HLXB9, and FOXA2 with or without islet coculture or islet-conditioned medium results in insulin gene expression. In conclusion, our results demonstrated that in vitro human bone marrow stem cells are able to differentiate into insulin-expressing cells by a mechanism involving several transcription factors of the beta-cell developmental pathway when cultured in an appropriate microenvironment. Stem Cells 2005;23:594-604

Betacellulin Overexpression in Mesenchymal Stem Cells Induces Insulin Secretion In Vitro and Ameliorates Streptozotocin-Induced Hyperglycemia in Rats

“…other important pancreas transcription factors, and the consequent production of insulin in agreement with Moriscot's conclusions about MSCs [36]. We observed that the morphology of BTC-MSCs changed from spindle-like to flat epithelial-like cells.…”

Generation and expansion of multipotent mesenchymal progenitor cells from cultured human pancreatic islets

“…Fibroblast-like cells emerging from pancreatic islets have been shown to be able to differentiate into insulin-expressing cells. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] To evaluate the ability of hPIDM cells to differentiate into a pancreatic endocrine phenotype, cells were cultured for 21 days in a medium for endocrine differentiation. Under these conditions, cells formed clusters that remained adherent to culture plates for the first week, but afterward detached acquiring an isletlike morphology (Figure 6a).…”

“…15 However, controversial data on the ability of mesenchymal stem cells to differentiate into insulin-producing cells both in vitro and in vivo have been reported. [19][20][21][22][23] Major interest has been recently raised by the evidence that insulinproducing cells can be obtained following the in vitro expansion of an intermediate mesenchymal proliferating cell population apparently derived from a reversible epithelialmesenchymal transition of pancreatic b-cells. 24, 25 Similar results have been obtained from the exocrine compartment of human pancreas.…”

Alleviation of hyperglycemia in diabetic rats by intraportal injection of insulin-producing cells generated from surgically resected human pancreatic tissue

“…In ex vivo regeneration therapy, the patients' own bone marrow stem cells are transiently removed and differentiated into b-cells in vitro (Lechner & Habener 2003, Moriscot et al 2005 whereas in vivo regeneration therapy uses the patients' own cells to regenerate impaired tissues (Zulewski et al 2001, Gao et al 2003. In vivo regeneration therapy is more cost-effective, has fewer side effects, and is more ethically and clinically acceptable; therefore, it may offer the greatest potential therapeutic value to diabetic patients, if effective protocols could be developed.…”