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Reprogram gastric tissue to functional insulin-secreting cells

将胃组织重新编程为功能性胰岛素分泌细胞

基本信息

批准号：
9221317
负责人：
Qiao Joe Zhou
金额：
$ 46.61万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9221317
关键词：
Acinar Cell Address Adult Animal Model Animals Antral Beta Cell Biological Assay C-Peptide Cadaver Cell Transplantation Cells Combined Modality Therapy Defect Development Endocrine Enteroendocrine Cell Epithelium Foundations Gastric Tissue Gastric mucosa Gene Activation Genes Genetic Genetic Transcription Glucose Goals HNF4A gene Human Hyperglycemia Individual Insulin Insulin-Dependent Diabetes Mellitus Intestines Investigation Kidney Laboratories Longevity Methods Molecular Mus NPM1 gene Organoids Pancreas Physiological Process Regenerative Medicine Risk Signal Pathway Source Stomach Structure Structure of beta Cell of islet Technology Teratoma Testing Therapeutic Thyroid Hormones Tissues Transforming Growth Factor beta Transgenic Organisms Transplantation Tretinoin base diabetic embryonic stem cell in vivo islet loss of function mutation neonatal diabetes mellitus new technology notch protein novel novel strategies polypeptide C public health relevance regenerative translational study

项目摘要

DESCRIPTION (provided by applicant): One major goal of regenerative medicine is to produce insulin secreting β-cells for transplantation therapy to treat Type 1 diabetes (T1D). Differentiation of embryonic stem cells is a powerful technology to generate functional insulin+ cells. However, teratoma formation is a serious concern with this approach. Alternatively, adult tissues could be converted into insulin+ cells in a process termed reprogramming. Reprogramming adult cells carries little risk for teratoma, but the reprogramming efficiency tends to be low and the resulting insulin+ cells have limited functionality. There is a critical ned to define the best tissue source and reprogramming method for this approach. My laboratory pioneered a reprogramming method based on a cocktail of defined genetic factors (Ngn3, Pdx1, Mafa, referred to as NPM factors). NPM factors are sufficient to convert pancreatic acinar cells to stable and functional insulin+ cells in animal models. In a comprehensive screen of adult tissues, we discovered that cells residing in the adult gastric mucosa also respond rapidly to NPM factors and generate functional insulin+ cells. Significantly, gastric insulin+ cells become glucose responsive faster than acinar-derived insulin+ cells. Thus, gastric tissue is a highly promising adult tissue source to produce functional insulin+ cells. Importantly, human gastric cells can be cultured and propagated as organoids in large numbers from cadaveric sources. Delivery of NPM factors led to formation of c-peptide+ cells in the human organoids, raising the exciting possibility of generating functional human insulin+ cells with this approach. One major aim of the proposal is to gain deeper understanding of the reprogramming process and the resulting gastric insulin+ cells. Specifically, we will determine the molecular and functional similarity of the induced gastric insulin+ cells with native islet beta-cells. We will investigate stability of the induced cells and test the hypothesis that islet structure formation will lead to heir long-term stability. We will also define the individual function of NPM factors in the reprogramming process. The second major aim of the proposal is to develop methods for efficient induction of functional insulin+ cells from human gastric tissues with combined treatment of genetic factors and signaling pathway modulators. Together, these studies will provide the necessary foundation for developing a novel technology to produce functional human insulin+ cells for therapeutic transplantation.

描述（由申请人提供）：再生医学的一个主要目标是产生胰岛素分泌β细胞，用于治疗1型糖尿病（T1D）的移植治疗。胚胎干细胞的分化是产生功能性胰岛素+细胞的强大技术。然而，畸胎瘤的形成是这种方法的一个严重问题。或者，成年组织可以在称为重编程的过程中转化为胰岛素+细胞。重编程成体细胞对畸胎瘤的风险很小，但重编程效率往往很低，所得的胰岛素+细胞功能有限。有一个关键的ned，以确定最佳的组织来源和重新编程的方法，这种方法。我的实验室开创了一种基于特定遗传因子（Ngn 3，Pdx 1，Mafa，称为NPM因子）混合物的重编程方法。NPM因子足以在动物模型中将胰腺腺泡细胞转化为稳定和功能性胰岛素+细胞。在对成人组织的全面筛选中，我们发现成人胃粘膜中的细胞也对NPM因子迅速反应并产生功能性胰岛素+细胞。值得注意的是，胃胰岛素+细胞比腺泡衍生的胰岛素+细胞更快地变得葡萄糖应答。因此，胃组织是产生功能性胰岛素+细胞的非常有前途的成人组织来源。重要的是，人胃细胞可以从尸体来源大量培养和繁殖为类器官。NPM因子的递送导致在人类类器官中形成c肽+细胞，提高了用这种方法产生功能性人类胰岛素+细胞的令人兴奋的可能性。该提案的一个主要目的是更深入地了解重编程过程和由此产生的胃胰岛素+细胞。具体而言，我们将确定诱导的胃胰岛素+细胞与天然胰岛β细胞的分子和功能相似性。我们将研究诱导细胞的稳定性，并测试胰岛结构形成将导致其长期稳定性的假设。我们还将定义NPM因子在重编程过程中的个体功能。该提案的第二个主要目的是开发从人胃组织中有效诱导功能性胰岛素+细胞的方法，并联合治疗遗传因子和信号传导通路调节剂。总之，这些研究将为开发一种新技术提供必要的基础，以生产用于治疗性移植的功能性人胰岛素+细胞。