PANCREATIC ISLET-DERIVED STEM CELLS

胰岛干细胞

• 批准号: 6368545
• 负责人: JOEL F HABENER
• 金额: $ 17.3万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-20 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6368545
• 关键词: NOD mouse; diabetes mellitus therapy; human tissue; immunosuppression; laboratory mouse; neurofilament proteins; nonhuman therapy evaluation; pancreatic islet function; pancreatic islet transplantation; pancreatic islets; stem cell transplantation; stem cells; streptozotocin; tissue /cell preparation

DESCRIPTION (provided by applicant): Sixteen million individuals in the USA suffer from diabetes mellitus, 1-2 million of which have type 1 (juvenile) diabetes in which the insulin-producing f3-cells in the pancreas are nearly completely destroyed by autoimmunity. Attempts to successfully transplant islets to diabetic subjects have been largely disappointing. We hypothesize that the lack of successful engraftment is due to the situation in which mature Beta cells in the islets are mostly postmitotic, are undergoing senescence, and that successful engraftment requires the neogenesis of new B-cells from stem cells that reside within the islets. We have identified and isolated pleuripotential stem cells from rat and human pancreatic islets. Therefore we propose an eventual approach whereby freshly isolated islets are precultured for several days with growth factors to expand the population of stem cells in the islets prior to their transplantation. To justify such an approach we propose in this exploratory/developmental application to demonstrate successful engraftment of human islet-derived stem cells transplanted to streptozotocin-induced diabetic and NOD diabetic mice. In initial studies we have successfully isolated nestin-positive stem cells from human (and rat) pancreatic islets, have expanded them ex vivo, and have successfully engrafted them in nonimmunosuppressed C57B16 mice under the renal capsule. A remarkable property of these islet-derived stem cells is that they appear to be immunologically blinded, do not undergo graft rejection, and do not express either class I or class II major histocompatibility complex (MHC) antigens. Even more remarkable is that the human tissue grafts express both human-specific class I and class II antigens, but are recognized by the mouse as self and do not undergo host vs. graft rejection. Further, the human NIPs are pleuripotential they differentiate into hepatic, neural, ductal, hematopoietic and adipocyte tissues phenotypes. We propose in this exploratory! developmental research application that morphogens in the mesenchymal niche provided by the engraftment of NIPs under the renal capsule differentiated the NIPs into multiple tissues but are inappropriate for Beta-cell differentiation. As proposed in this application, transplantation of NIPs directly into the pancreata of STZ-induced and NOD diabetic mice will differentiate NIPs into Beta-cells and permanently cure the diabetes.

描述(申请人提供)：美国有1600万人患有糖尿病，其中100-200万人患有1型糖尿病(青少年) 糖尿病患者胰腺中产生胰岛素的f3细胞几乎 完全被自身免疫力摧毁了。尝试成功地进行移植 糖尿病患者的胰岛在很大程度上令人失望。我们假设 缺乏成功的植入是由于成熟的情况 胰岛中的β细胞大多是有丝分裂后的，正在经历衰老，并且 这种成功的植入需要从干细胞中新生的B细胞 位于胰岛内的细胞。我们已经确认并分离了 来自大鼠和人胰岛的胸膜潜能干细胞。因此我们 提出一种最终的方法，即预先培养新分离的胰岛 几天来用生长因子扩大干细胞的数量 移植前的胰岛。为了证明这种方法是合理的，我们 在此试探性/开发性应用中提出建议，以展示成功 人胰岛来源干细胞移植于人外周血中的植入 链脲佐菌素诱导的糖尿病和NOD糖尿病小鼠。在初步研究中，我们 已经成功地从人(和大鼠)中分离出Nestin阳性干细胞 胰岛，体外扩增，并成功植入 在非免疫抑制的C57B16小鼠肾被膜下。不同寻常的 这些来自胰岛的干细胞的特性是它们似乎是 免疫失明，不会发生移植物排斥反应，也不表达 I类或II类主要组织相容性复合体(MHC)抗原。 更值得注意的是，人类组织移植物既表达了 人类特有的I类和II类抗原，但可被小鼠识别 作为自身，不经历宿主对移植物的排斥反应。此外，人类的Nipp 它们分化为肝、神经、导管、 造血和脂肪细胞组织表型。我们在这个探索中提出了建议！ 形态因子在间充质生态位发育研究中的应用 通过在肾被膜下植入NIP来区分 夹入多个组织，但不适合β细胞分化。 如本申请中所建议的，将NIP直接移植到 STZ诱导和NOD糖尿病小鼠的胰腺将NIPs分化为 β细胞和永久治愈糖尿病。