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Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes

机译:从成年胰岛分离的多潜能巢蛋白阳性干细胞离体分化成胰腺内分泌,外分泌和肝表型

摘要

The endocrine cells of the rat pancreatic islets of Langerhans, including insulin-producing β-cells, turn over every 40-50 days by processes of apoptosis and the proliferation and differentiation of new islet cells (neogenesis) from progenitor epithelial cells located in the pancreatic ducts. However, the administration to rats of islet trophic factors such as glucose or glucagon-like peptide 1 for 48 h results in a doubling of islet cell mass, suggesting that islet progenitor cells may reside within the islets themselves. Here we show that rat and human pancreatic islets contain a heretofore unrecognized distinct population of cells that express the neural stem cell-specific marker nestin. Nestin-positive cells within pancreatic islets express neither the hormones insulin, glucagon, somatostatin, or pancreatic polypeptide nor the markers of vascular endothelium or neurons, such as collagen IV and galanin. Focal regions of nestin-positive cells are also identified in large, small, and centrolobular ducts of the rat pancreas. Nestin-positive cells in the islets and in pancreatic ducts are distinct from ductal epithelium because they do not express the ductal marker cytokeratin 19 (CK19). After their isolation, these nestin-positive cells have an unusually extended proliferative capacity when cultured in vitro (∼8 months), can be cloned repeatedly, and appear to be mnitipotential. Upon confluence, they are able to differentiate into cells that express liver and exocrine pancreas markers, such as α-fetoprotein and pancreatic amylase, and display a ductal/endocrine phenotype with expression of CK19, neural-specific cell adhesion molecule, insulin, glucagon, and the pancreas/duodenum specific homeodomain transcription factor, IDX-1. We propose that these nestin-positive islet-derived progenitor (NIP) cells are a distinct population of cells that reside within pancreatic islets and may participate in the neogenesis of islet endocrine cells. The NIP cells that also reside in the pancreatic ducts may be contributors to the established location of islet progenitor cells. The identification of NIP cells within the pancreatic islets themselves suggest possibilities for treatment of diabetes, whereby NIP cells isolated from pancreas biopsies could be expanded ex vivo and transplanted into the donor/recipient.
机译:朗格汉斯大鼠胰岛的内分泌细胞(包括产生胰岛素的β细胞)每40-50天通过凋亡过程以及来自胰祖细胞的新胰岛细胞的增殖和分化(新生)过程进行翻新。管道。但是,向大鼠施用48小时的胰岛营养因子(例如葡萄糖或胰高血糖素样肽1)会导致胰岛细胞量增加一倍,这表明胰岛祖细胞可能驻留在胰岛自身中。在这里,我们显示大鼠和人的胰岛包含迄今无法识别的表达神经干细胞特异性标志物Nestin的细胞群。胰岛中的巢蛋白阳性细胞既不表达胰岛素,胰高血糖素,生长抑素或胰多肽激素,也不表达血管内皮或神经元的标志物,例如IV型胶原蛋白和甘丙肽。还可以在大鼠胰腺的大,小和中心小叶导管中发现巢蛋白阳性细胞的焦点区域。胰岛和胰管中的巢蛋白阳性细胞不同于导管上皮,因为它们不表达导管标记物细胞角蛋白19(CK19)。分离后,这些Nestin阳性细胞在体外培养(约8个月)时具有异常扩展的增殖能力,可以重复克隆,并且具有记忆力。汇合后,它们能够分化为表达肝和外分泌胰腺标记物(例如α-甲胎蛋白和胰淀粉酶)的细胞,并表现出导管/内分泌表型,并表达CK19,神经特异性细胞粘附分子,胰岛素,胰高血糖素,胰/十二指肠特定同源域转录因子IDX-1。我们建议这些巢蛋白阳性胰岛来源的祖细胞(NIP)是驻留在胰岛内的细胞的独特群体,并可能参与胰岛内分泌细胞的新生。也位于胰管中的NIP细胞可能是胰岛祖细胞确定位置的原因。胰腺胰岛自身中NIP细胞的鉴定为糖尿病的治疗提供了可能性,因此从胰腺活检组织中分离出的NIP细胞可以离体扩增并移植到供体/受体中。

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