Tang Dong-Qi, Cao Li-Zhen, Burkhardt Brant R, Xia Chang-Qi, Litherland Sally A, Atkinson Mark A, Yang Li-Jun
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.
Diabetes. 2004 Jul;53(7):1721-32. doi: 10.2337/diabetes.53.7.1721.
Efforts toward routine islet cell transplantation as a means for reversing type 1 diabetes have been hampered by islet availability as well as allograft rejection. In vitro transdifferentiation of mouse bone marrow (BM)-derived stem (mBMDS) cells into insulin-producing cells could provide an abundant source of autologous cells for this procedure. For this study, we isolated and characterized single cell-derived stem cell lines obtained from mouse BM. In vitro differentiation of these mBMDS cells resulted in populations meeting a number of criteria set forth to define functional insulin-producing cells. Specifically, the mBMDS cells expressed multiple genes related to pancreatic beta-cell development and function (insulin I and II, Glut2, glucose kinase, islet amyloid polypeptide, nestin, pancreatic duodenal homeobox-1 [PDX-1], and Pax6). Insulin and C-peptide production was identified by immunocytochemistry and confirmed by electron microscopy. In vitro studies involving glucose stimulation identified glucose-stimulated insulin release. Finally, these mBMDS cells transplanted into streptozotocin-induced diabetic mice imparted reversal of hyperglycemia and improved metabolic profiles in response to intraperitoneal glucose tolerance testing. These results indicate that mouse BM harbors cells capable of in vitro transdifferentiating into functional insulin-producing cells and support efforts to derive such cells in humans as a means to alleviate limitations surrounding islet cell transplantation.
将常规胰岛细胞移植作为逆转1型糖尿病的一种手段的努力，一直受到胰岛供应以及同种异体移植排斥反应的阻碍。小鼠骨髓（BM）来源的干细胞（mBMDS）细胞在体外转分化为胰岛素生成细胞可为该程序提供丰富的自体细胞来源。在本研究中，我们分离并鉴定了从小鼠BM获得的单细胞来源的干细胞系。这些mBMDS细胞在体外分化产生的细胞群体符合为定义功能性胰岛素生成细胞而设定的多项标准。具体而言，mBMDS细胞表达了多个与胰腺β细胞发育和功能相关的基因（胰岛素I和II、Glut2、葡萄糖激酶、胰岛淀粉样多肽、巢蛋白、胰腺十二指肠同源盒-1 [PDX-1]和Pax6）。通过免疫细胞化学鉴定胰岛素和C肽的产生，并通过电子显微镜进行确认。涉及葡萄糖刺激的体外研究确定了葡萄糖刺激的胰岛素释放。最后，将这些mBMDS细胞移植到链脲佐菌素诱导的糖尿病小鼠中，可使高血糖症得到逆转，并改善腹腔葡萄糖耐量试验的代谢状况。这些结果表明，小鼠BM中含有能够在体外转分化为功能性胰岛素生成细胞的细胞，并支持在人类中获得此类细胞的努力，以此作为减轻胰岛细胞移植相关限制的一种手段。
