Mechanisms of Cell Regeneration in the Pancreas

胰腺细胞再生的机制

• 批准号: 8120419
• 负责人: Maike Sander
• 金额: $ 28.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120419
• 关键词: Ablation; Adult; Apoptosis; Beta Cell; Birth; Cadaver; Cell Differentiation process; Cell Maintenance; Cell Proliferation; Cell Transplantation; Cell Transplants; Cell physiology; Cells; Characteristics; Development; Diabetes Mellitus; Duct (organ) structure; Ductal; Ductal Epithelial Cell; Embryo; Embryo Loss; Fluorescence-Activated Cell Sorting; Gene Dosage; Genes; Green Fluorescent Proteins; Immune response; Injury; Insulin; Islet Cell; Label; Life; Maintenance; Modeling; Molecular; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pancreatectomy; Pancreatic Injury; Patients; Phenotype; Physiological; Play; Population; Property; Replacement Therapy; Research Personnel; Role; Sorting - Cell Movement; Source; Staging; Stem cells; Streptozocin; Structure of beta Cell of islet; Testing; Tissues; Transplantation; Undifferentiated; base; blastomere structure; cell type; emerging adult; fetal; islet; pancreas development; progenitor; programs; research study; response to injury; stem; transcription factor

DESCRIPTION (provided by applicant): The overall objective of this proposal is to identify and characterize putative stem/progenitor cells in the adult pancreas. The identification of such cells would facilitate the development of a cell replacement therapy for patients with diabetes. Such therapy, though highly effective, is currently limited by the shortage of transplantable islets from cadaver tissue. Adult progenitors would be a particularly attractive source for the differentiation of replacement insulin-producing beta-cells, as they could possibly be isolated from the patient's own pancreas, thereby avoiding the immune response associated with the transplantation of foreign tissue. It is, however, still unclear whether a stem or progenitor cell population resides in the pancreas beyond the embryonic period. In preliminary studies, we have identified the transcription factor SOX9 as a marker for progenitor cells in the embryonic pancreas and found that Sox9 is essential for their expansion and maintenance. Strikingly, its expression persists in the adult pancreas exclusively in a subset of ductal cells; a cell type that is regarded as a potential reservoir of pancreatic stem/progenitor cells. Given the crucial role of SOX9 in maintaining undifferentiated, pluripotent progenitors of the embryonic pancreas, we hypothesize that this factor also marks and maintains a stem cell compartment in the adult pancreas. Experiments are proposed to test whether SOX9 plays a role in pancreas regeneration and whether the cells marked by SOX9 in adult pancreas can function as pluripotent pancreas progenitor cells. Using inducible gene ablation, Aim 1 is to define the role of Sox9 in pancreatic cell differentiation and maintenance throughout development and adulthood. Aim 2 examines if Sox9 is required for pancreas regeneration after partial pancreatectomy or STZ treatment. Aim 3 will define whether Sox9-expressing cells have characteristics and properties of multipotential stem/progenitor cells. This will be tested by transcriptional profiling of isolated cells and by tracking their fate in cell transplantation experiments.

描述（由申请人提供）：该提案的总体目标是鉴定和表征成体胰腺中假定的干/祖细胞。此类细胞的鉴定将有助于糖尿病患者细胞替代疗法的开发。这种疗法虽然非常有效，但目前由于尸体组织中可移植胰岛的短缺而受到限制。成年祖细胞对于分化替代性产生胰岛素的β细胞来说是一个特别有吸引力的来源，因为它们可以从患者自己的胰腺中分离出来，从而避免与外来组织移植相关的免疫反应。然而，目前尚不清楚胚胎期之后胰腺中是否存在干细胞或祖细胞群。在初步研究中，我们已经确定转录因子 SOX9 作为胚胎胰腺中祖细胞的标记，并发现 Sox9 对于它们的扩张和维持至关重要。引人注目的是，它的表达仅在成人胰腺的导管细胞亚群中持续存在。一种被视为胰腺干/祖细胞潜在储存库的细胞类型。鉴于 SOX9 在维持胚胎胰腺未分化、多能祖细胞中的关键作用，我们假设该因子也标记并维持成人胰腺中的干细胞区室。拟通过实验来测试SOX9是否在胰腺再生中发挥作用，以及成人胰腺中SOX9标记的细胞是否可以充当多能胰腺祖细胞。使用诱导基因消融，目标 1 是确定 Sox9 在整个发育和成年期胰腺细胞分化和维持中的作用。目标 2 检查部分胰腺切除术或 STZ 治疗后胰腺再生是否需要 Sox9。目标 3 将确定表达 Sox9 的细胞是否具有多能干/祖细胞的特征和特性。这将通过分离细胞的转录谱和细胞移植实验中追踪它们的命运来进行测试。