PANCREATIC ISLET-DERIVED STEM CELLS

胰岛干细胞

• 批准号: 6524424
• 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6524424
• 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（由申请人提供）：美国1600万个人患有糖尿病，其中1-200万人有1型（少年） 胰腺中产生胰岛素F3细胞的糖尿病几乎是 完全被自身免疫所破坏。尝试成功移植的尝试 糖尿病学科的胰岛基本上令人失望。我们假设 缺乏成功的植入是由于成熟的情况 胰岛中的β细胞主要是有丝分裂的，正在经历衰老，并且 成功的植入需要从茎中进行新的B细胞新作用 位于胰岛内的细胞。我们已经确定并隔离了 来自大鼠和人类胰岛的胸膜干细胞。因此我们 提出一种最终的方法，从而使新隔离的小岛被预先培养 几天以来，生长因素扩大了干细胞中的人群 胰岛移植之前。为了证明这种方法是合理的 在此探索性/发展应用中提出建议证明成功 移植到移植到的人类胰岛源性干细胞 链蛋白酶诱导的糖尿病和点头糖尿病小鼠。在最初的研究中我们 已经成功地分离了与人（和大鼠）的巢蛋白阳性干细胞 胰岛胰岛已将其扩展到体内，并成功地植入了 它们在肾囊下的非免疫抑制的C57B16小鼠中。一个了不起的 这些小岛衍生的干细胞的特性是它们似乎是 免疫学上盲目，不要接受移植拒绝，也不表达 I类或II类主要组织相容性复合物（MHC）抗原。 更显着的是，人体组织移植物表达 人类特异性的I类和II类抗原，但被鼠标识别 作为自我，不接受宿主与嫁接的拒绝。此外，人类的nip 它们是否会分化为肝，神经，导管， 造血和脂肪细胞组织表型。我们在此探索性中提出建议！ 在间充质细分市场中形成的发展研究应用 由肾囊下的nip植入的植物提供了区分 将nips成多个组织，但不适合β细胞分化。 正如本应用程序所提出的那样，将NIP直接移植到 STZ诱导和点头糖尿病小鼠的胰腺将使NIP区分为 β细胞并永久治愈糖尿病。