Improving human pluripotent stem cell derived beta cell transplantation using genetic lineage tracing.

使用遗传谱系追踪改善人类多能干细胞衍生的β细胞移植。

• 批准号: 9788443
• 负责人: Holger A. Russ
• 金额: $ 38.54万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788443
• 关键词: Address; Adopted; Adoption; Amino Acids; Animal Model; Apoptotic; Applications Grants; Autoimmune Process; Automobile Driving; BCL2 gene; Beta Cell; Cadaver; Cell Death; Cell Survival; Cell Therapy; Cell Transplantation; Cell Transplants; Cell physiology; Cells; Cessation of life; Communities; Complement; Diabetes Mellitus; Disease; Encapsulated; Engraftment; Event; Genetic; Genome engineering; Goals; Graft Survival; Grant; Hormones; Human; Hypoglycemia; Hypoxia; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Islets of Langerhans Transplantation; Knowledge; Mediating; Messenger RNA; Methods; Molecular; Molecular Analysis; Oxygen; Patients; Performance; Phase; Phenotype; Physiological; Process; Quality of life; Replacement Therapy; Research; Risk; Source; Stem cells; Supplementation; Therapeutic Studies; Time; Transplantation; base; beta cell replacement; cell type; clinically translatable; deprivation; experience; experimental study; functional loss; glucose production; graft function; human pluripotent stem cell; improved; in vivo; islet; large scale production; neglect; nutrient deprivation; nutrition; post-transplant; preservation; prevent; therapy outcome; transdifferentiation; virtual

Project summary: Type one diabetes (T1D) is characterized by the destruction of insulin-producing beta cells by an autoimmune attack. Currently there is no cure available and T1D patients rely on supply of endogenous insulin via injections, but long-term complications and the risk of hypoglycemia due to poor insulin control persist. Transplantation of isolated cadaveric islets into long-standing T1D patients results in ~35 months of insulin independence, tremendously improving quality of life. While this beta cell replacement therapy has emerged as a potential cure for T1D, its advancement has been hampered by the lack of an abundant beta cell source. We have recently demonstrated the large-scale production of glucose responsive insulin producing beta-like cells from human pluripotent stem cells. These cells can correct diabetes in animal models, thus directly addressing donor shortage with this viable approach. However, a largely neglected aspect of current cell therapy research efforts is the dramatic and immediate loss of stem cell derived beta cells (sBCs) upon transplantation. This is a critical problem that, if successfully resolved, will tremendously increase the efficacy of virtually all current approaches proposing to deliver sBCs for cell replacement therapy purposes, both naked and encapsulated. Our overall hypothesis is that transplantation of sBCs results in the loss of a large proportion of these cells, due to several mechanisms, including: (1) hypoxia and nutrition deprivation mediated cell death, (2) transdifferentiate into other hormone expressing cell types and (3) that part of the remaining sBCs adopt a less functional beta cell phenotype. The focus of this grant application is two-fold: (1) accurately and comprehensively elucidate the fate of sBCs upon transplantation employing genetic lineage tracing and (2) to prevent phenotypical changes and sBC death by temporal expression of the anti-apoptotic gene BCL2 using mRNAs in combination with physiological oxygen adaption shown by us to significantly improve graft survival. Specifically, our lineage tracing analysis will comprehensively define the cellular changes of sBC upon transplantation. We further anticipate to accurately define the associated molecular changes driving them, thus likely providing unacknowledged targets to improve sBC survival thereafter. Furthermore, we except to provide an effective and simple way to prevent the loss of functional sBC mass that is currently occurring upon transplantation. Taken together, the timely approach outlined within this proposal combined with our unique expertise is poised to successfully address a critical problem of cell replacement therapy for T1D patients, the preservation of sBC survival and function immediately upon transplantation.

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