Human beta-cell precursors mature into functional insulin-producing cells in an immunoisolation device: implications for diabetes cell therapies.
Human beta-cell precursors mature into functional insulin-producing cells in an immunoisolation device: implications for diabetes cell therapies.
复制标题
DOI：
10.1097/tp.0b013e31819c86ea
复制
发表时间：
2009-04-15
期刊：
影响因子：
6.2
通讯作者：
Itkin-Ansari P
中科院分区：
文献类型：
--
作者：
Lee SH;Hao E;Savinov AY;Geron I;Strongin AY;Itkin-Ansari P
胰岛移植受到慢性免疫抑制和供体组织缺乏的限制。随着人类β细胞新来源的开发（例如，干细胞来源的组织），将它们移植到耐用的装置中可以避免免疫抑制的需要，同时也可以保护患者免受任何致瘤性风险。在这里，我们研究了(1)包裹的人β-细胞及其祖细胞的存活和功能，以及(2)包裹的鼠β-细胞在同种异体和自身免疫环境中的植入。将人胰岛和人胎儿胰岛样细胞团包裹在聚四氟乙烯装置（TheraCyte）中，移植到免疫缺陷小鼠体内。通过免疫组织化学、循环人c肽水平和血糖水平测量移植物的存活和功能。采用生物发光成像技术监测被包封的新生鼠胰岛。被包裹的人胰岛样细胞簇存活、复制，并获得足够水平的葡萄糖反应性胰岛素分泌，以改善糖尿病小鼠的高血糖。包裹的小鼠新生胰岛的生物发光成像揭示了细胞死亡后再生长的动态过程，导致同种异体移植物长期存活。此外，在I型糖尿病的非肥胖糖尿病（NOD）小鼠模型中，包封的原代β细胞在不刺激可检测到的t细胞反应的情况下改善了糖尿病。我们首次证明，人类β细胞的功能是兼容的封装在一个持久的，免疫保护装置。此外，我们的研究表明，在终末分化之前对β细胞进行包封将是一种成功的方法，可以用于新的基于细胞的糖尿病治疗，例如来自干细胞的治疗。
Islet transplantation is limited by the need for chronic immunosuppression and the paucity of donor tissue. As new sources of human β-cells are developed (e.g., stem cell-derived tissue), transplanting them in a durable device could obviate the need for immunosuppression, while also protecting the patient from any risk of tumorigenicity. Here, we studied (1) the survival and function of encapsulated human β-cells and their progenitors and (2) the engraftment of encapsulated murine β-cells in allo- and autoimmune settings. Human islets and human fetal pancreatic islet-like cell clusters were encapsulated in polytetrafluorethylene devices (TheraCyte) and transplanted into immunodeficient mice. Graft survival and function was measured by immunohistochemistry, circulating human C-peptide levels, and blood glucose levels. Bioluminescent imaging was used to monitor encapsulated neonatal murine islets. Encapsulated human islet-like cell clusters survived, replicated, and acquired a level of glucose responsive insulin secretion sufficient to ameliorate hyperglycemia in diabetic mice. Bioluminescent imaging of encapsulated murine neonatal islets revealed a dynamic process of cell death followed by regrowth, resulting in robust long-term allograft survival. Further, in the non-obese diabetic (NOD) mouse model of type I diabetes, encapsulated primary β-cells ameliorated diabetes without stimulating a detectable T-cell response. We demonstrate for the first time that human β-cells function is compatible with encapsulation in a durable, immunoprotective device. Moreover, our study suggests that encapsulation of β-cells before terminal differentiation will be a successful approach for new cell-based therapies for diabetes, such as those derived from stem cells.