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）：美国有1600万人 患有糖尿病，其中1-2百万人患有1型糖尿病（青少年） 糖尿病，其中胰腺中产生胰岛素的f3细胞几乎 被自身免疫完全摧毁尝试成功移植 糖尿病患者的胰岛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下， 胰岛中的β细胞大多处于有丝分裂后，正在经历衰老， 成功的移植需要从干细胞中新生出新的B细胞， 这些细胞位于胰岛内。我们已经识别并分离出 来自大鼠和人类胰岛的多能干细胞。因此我们 提出了一种最终的方法，即将新鲜分离的胰岛预培养 用生长因子培养几天， 在移植之前，为了证明这种做法的合理性， 在此探索性/开发性应用中提出， 移植人胰岛源性干细胞， 链脲佐菌素诱导的糖尿病和NOD糖尿病小鼠。在最初的研究中， 成功地从人类（和大鼠）中分离出nestin阳性干细胞 胰岛，已经将它们体外扩增，并且已经成功地植入 它们在非免疫抑制的C57 B16小鼠的肾包膜下。一个了不起 这些胰岛衍生干细胞的特性是它们似乎是 免疫盲法，不经历移植排斥，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，人类组织移植物表达了 人特异性I类和II类抗原，但被小鼠识别 作为自身并且不经历宿主与移植物排斥。此外，人类NIP 是胸膜能的，它们分化成肝的、神经的、导管的， 造血和脂肪细胞组织表型。我们建议在此探索！ 形态发生素在间充质生态位发育研究中应用 通过在肾包膜下植入NIP， NIP进入多种组织，但不适合β细胞分化。 如本申请中所提出的，将NIP直接移植到 STZ诱导的和NOD糖尿病小鼠的胰腺将NIP分化为 β细胞和永久治愈糖尿病。