Insulin Producing Cells from Amniotic Stem Cells for Diabetes Therapy

羊膜干细胞产生胰岛素的细胞用于糖尿病治疗

基本信息

批准号：
7880311
负责人：
ANTHONY ATALA
金额：
$ 3.88万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7880311
关键词：
Address Affect Allogenic Amniocentesis Amniotic Fluid Autologous Autologous Transplantation Beta Cell C-Peptide Cell Differentiation process Cell Line Cell Lineage Cell Therapy Cell Transplantation Cells Clinical Clonal Expansion Development Diabetes Mellitus Disease Embryo Face Germ Layers Goals Growth Factor Health Care Costs Hormones Human Immunodeficient Mouse Immunosuppression Immunosuppressive Agents Implant In Vitro Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Kidney Failure Laboratories Medical Modeling Mothers Mus Neuropathy Non-Insulin-Dependent Diabetes Mellitus Organ Donor Pancreas Patients Pharmaceutical Preparations Phase Phenotype Plasmid Cloning Vector Pluripotent Stem Cells Population Production Program Development Public Health Regulator Genes Research Retinal Diseases Source Stem cells Streptozocin Structure of beta Cell of islet System Testing Transplantation Treatment Protocols Vascular Diseases amniotic fluid derived stem cell base blood glucose regulation cell type clinically relevant diabetes mellitus therapy diabetic falls glucose metabolism human embryonic stem cell improved in vivo insulin secretion islet meetings nonhuman primate novel offspring patient population pre-clinical pregnant prevent progenitor programs quantum research study stem stem cell differentiation transcription factor vector

项目摘要

DESCRIPTION (provided by applicant): Diabetes mellitus is a growing problem worldwide. In the US it affects over 18 million people and results in annual health care costs exceeding $130 billion. Insulin therapy of Type 1 diabetes, and in advanced cases of Type 2 diabetes, does not prevent serious long-term complications including neuropathy, vascular disease, retinopathy and renal failure. Transplantation of pancreatic islets to restore insulin production offers significant promise. However, the supply of donor pancreata falls far short of meeting the medical need. New sources of insulin producing cells will be required to realize the full potential of cell therapy for diabetes. We propose to generate pancreatic beta lineage cells by in vitro differentiation of stem cells isolated from amniotic fluid. These "AFS cells" are capable of both extensive expansion and differentiation into derivatives of all three embryonic germ layers. Our Preliminary Studies showed that mouse AFS cells can yield insulin producing cells and islet-like cell clusters ("neo-islets"), promoted by expression of the pancreatic transcription factor PDX-1. We now propose to produce neo-islets from human and non-human primate (NHP) AFS cells. To efficiently generate insulin producing cells, we will optimize delivery of a plasmid vector to express PDX-1, and will systematically test growth factors and substrates shown previously to promote pancreatic beta cell differentiation. The resulting neo-islets will be compared with authentic human and NHP pancreatic islets using tests developed for clinical transplantation. To assess their ability to restore control of glucose metabolism and production of insulin and C-peptide, neo-islets will be implanted in immunodeficient mice made diabetic with streptozotocin (STZ). Transplantation in STZ-treated NHP will assess the function of neo-islets in a model physiologically more similar to humans. NHP AFS cell lines will be derived after amniocentesis of pregnant mothers. These stem cells will be used to generate neo-islets for autologous transplantation into the corresponding offspring. The same donor cells will be compared in allogeneic recipients using clinically relevant immunosuppression regimens. Successful development of an abundant source of transplantable insulin producing cells potentially would have a profound impact on the treatment of a major public health problem.

描述（由申请人提供）：糖尿病是全球越来越多的问题。在美国，它影响了超过1800万人，并导致年度医疗保健成本超过1300亿美元。 1型糖尿病的胰岛素治疗以及2型糖尿病的晚期病例，不能阻止严重的长期并发症，包括神经病，血管疾病，视网膜病变和肾衰竭。胰岛移植以恢复胰岛素的生产，这带来了巨大的希望。但是，供体胰腺的供应远远无法满足医疗需求。将需要新的胰岛素产生细胞来实现糖尿病细胞疗法的全部潜力。我们建议通过从羊水分离的干细胞的体外分化来产生胰腺β谱系细胞。这些“ AFS细胞”能够广泛扩展和分化为所有三个胚胎细菌层的衍生物。我们的初步研究表明，小鼠AFS细胞可以通过胰腺转录因子PDX-1的表达来促进胰岛素产生胰岛素和胰岛样细胞簇（“ Neo-Islets”）。现在，我们建议从人类和非人类灵长类动物（NHP）AFS细胞中产生新islet。为了有效地产生胰岛素产生细胞，我们将优化质粒载体的递送以表达PDX-1，并将系统地测试先前显示的生长因子和底物，以促进胰腺β细胞分化。将使用用于临床移植的测试，将所得的新islet与正宗的人和NHP胰岛进行比较。为了评估他们恢复对葡萄糖代谢的控制能力以及胰岛素和C肽的产生，新尿素将植入与链霉菌素（STZ）糖尿病的免疫缺陷小鼠中。在经STZ处理的NHP中移植将评估新islets在生理上与人类更相似的模型中的功能。 NHP AFS细胞系将在怀孕母亲的羊膜穿刺术后得出。这些干细胞将用于生成新islet，以自体移植到相应的后代。使用临床相关的免疫抑制方案，将在同种异体受体中比较相同的供体细胞。成功地发展了大量可移植胰岛素产生的细胞的来源可能会对对重大公共卫生问题的治疗产生深远的影响。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic modification of primate amniotic fluid-derived stem cells produces pancreatic progenitor cells in vitro.

DOI：
10.1159/000345816
发表时间：
2013
期刊：
Cells, tissues, organs
影响因子：
0
作者：
Zhou Y;Mack DL;Williams JK;Mirmalek-Sani SH;Moorefield E;Chun SY;Wang J;Lorenzetti D;Furth M;Atala A;Soker S
通讯作者：
Soker S

Porcine pancreas extracellular matrix as a platform for endocrine pancreas bioengineering.

DOI：
10.1016/j.biomaterials.2013.03.054
发表时间：
2013-07
期刊：
BIOMATERIALS
影响因子：
14
作者：
Mirmalek-Sani, Sayed-Hadi;Orlando, Giuseppe;McQuilling, John P.;Pareta, Rajesh;Mack, David L.;Salvatori, Marcus;Famey, Alan C.;Stratta, Robert J.;Atala, Anthony;Opara, Emmanuel C.;Soker, Shay
通讯作者：
Soker, Shay

Bioprinted amniotic fluid-derived stem cells accelerate healing of large skin wounds.