Zulewski H, Abraham E J, Gerlach M J, Daniel P B, Moritz W, Müller B, Vallejo M, Thomas M K, Habener J F
Division of Endocrinology and Diabetes, University Hospital of Geneva, Switzerland.
Diabetes. 2001 Mar;50(3):521-33. doi: 10.2337/diabetes.50.3.521.
The endocrine cells of the rat pancreatic islets of Langerhans, including insulin-producing beta-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 (approximately 8 months), can be cloned repeatedly, and appear to be multipotential. Upon confluence, they are able to differentiate into cells that express liver and exocrine pancreas markers, such as alpha-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.
大鼠胰岛的内分泌细胞，包括产生胰岛素的β细胞，每40 - 50天通过凋亡以及位于胰腺导管中的祖上皮细胞产生新的胰岛细胞（新生）的增殖和分化过程进行更新。然而，给大鼠注射胰岛营养因子如葡萄糖或胰高血糖素样肽1达48小时会导致胰岛细胞质量加倍，这表明胰岛祖细胞可能存在于胰岛自身内部。在此我们表明，大鼠和人类的胰岛含有一种迄今未被认识的独特细胞群体，它们表达神经干细胞特异性标志物巢蛋白。胰岛内的巢蛋白阳性细胞既不表达胰岛素、胰高血糖素、生长抑素或胰多肽等激素，也不表达血管内皮或神经元的标志物，如IV型胶原和甘丙肽。在大鼠胰腺的大、小和中央小叶导管中也发现了巢蛋白阳性细胞的局灶区域。胰岛和胰腺导管中的巢蛋白阳性细胞与导管上皮不同，因为它们不表达导管标志物细胞角蛋白19（CK19）。分离后，这些巢蛋白阳性细胞在体外培养时具有异常延长的增殖能力（约8个月），可以反复克隆，并且似乎具有多能性。汇合后，它们能够分化为表达肝脏和外分泌胰腺标志物的细胞，如甲胎蛋白和胰淀粉酶，并表现出导管/内分泌表型，表达CK19、神经特异性细胞粘附分子、胰岛素、胰高血糖素以及胰腺/十二指肠特异性同源结构域转录因子IDX - 1。我们提出，这些巢蛋白阳性的胰岛衍生祖细胞（NIP细胞）是存在于胰岛内的独特细胞群体，可能参与胰岛内分泌细胞的新生。同样存在于胰腺导管中的NIP细胞可能是胰岛祖细胞既定位置的贡献者。在胰岛自身内部鉴定出NIP细胞提示了糖尿病治疗的可能性，即从胰腺活检中分离出的NIP细胞可以在体外扩增并移植回供体/受体。
