Identification and Characterization of the Presomitic Mesoderm Progenitor

前体中胚层祖细胞的鉴定和表征

• 批准号: 8386231
• 负责人: CRAIG E NELSON
• 金额: $ 21.25万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386231
• 关键词: Affect; Anatomy; Arthritis; Biology; Blood; Cardiovascular system; Cartilage; Cells; Clinical; Congenital Abnormality; Connective Tissue; Data; Derivation procedure; Disease; Embryo; Foundations; Generations; Goals; Grant; Hensen' s Node; In Situ Hybridization; In Vitro; Knowledge; Maintenance; Mammals; Mesoderm; Mesoderm Cell; Molecular; Molecular Profiling; Mus; Muscle; Musculoskeletal; Musculoskeletal Diseases; Osteoporosis; Paraxial Mesoderm; Pathway interactions; Patients; Population; Primitive Streaks; Procedures; Protocols documentation; Regenerative Medicine; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Somites; Stem cells; Testing; Tissues; Transcript; Tretinoin; Wasting Syndrome; Work; Wound Healing; base; cell type; embryonic stem cell; human disease; human embryonic stem cell; improved; induced pluripotent stem cell; insight; molecular marker; novel strategies; progenitor; public health relevance; regenerative; single cell analysis; tissue culture; tissue regeneration

DESCRIPTION (provided by applicant): Diseases of the mesodermal tissues of the body including wound healing, arthritis, osteoporosis and muscular wasting diseases, affect millions of people across the globe. If existing barriers to the efficient derivation of mesodermal tissues from readily-available, patient-matched stem cells could be overcome, these diseases could be treated with stem cell-based regenerative medicine. Unfortunately, robust directed differentiation of mesoderm from embryonic stem cells (ESC) and induced pluripotent stem cells (IPSC) is currently limited to cardiovascular and blood derivatives. Reproducible protocols for the differentiation of muscle, cartilage, and connective tissues, or more specifically, those mesodermal derivatives produced solely from pre-somitic mesoderm (PSM), have yet to emerge. While it is possible to obtain some cell types of the posterior mesoderm from human ESC, these efficiencies (commonly <1%) must be vastly improved before regenerative procedures for these tissues will be feasible. Previous studies have indicated the presence of an endogenous PSM-progenitor (PSM-Pr) cell located at the border of the primitive streak and Hensen's node (the PSM-Pr niche). Progeny of the PSM-Pr colonize the paraxial mesoderm and give rise to the somites, which in turn produce the skeletal muscle, cartilage, and connective tissue of the embryo. The primary focus of the work described here is to identify and exhaustively characterize the cell types that comprise and maintain the endogenous progenitor stem cell and its niche. In this project we will (1) identify all cell types located in the border region and (2) evaluate the role of key signaling pathways in the maintenance of the PSM-Pr and the PSM-Pr niche. Successful completion of these goals will provide unprecedented insight into the generation of somitic mesoderm and enable novel approaches to the generation of therapeutically relevant mesodermal cell types for clinical use. PUBLIC HEALTH RELEVANCE: The goals of this exploratory grant are to identify the long-term progenitor of the pre-somitic mesoderm and characterize functions required for the maintenance of this cell type and its niche. This knowledge will provide important insight into the generation of vertebrate axial mesoderm and, therefore, also into musculoskeletal birth defects and human disease. Moreover, identification and characterization of the PSM-Pr and its niche will provide a foundation for the guided differentiation of mesodermal derivatives for the treatment of musculoskeletal disorders including, wound healing, arthritis, osteoporosis, and muscle wasting diseases.

描述（由申请人提供）：身体中表皮组织疾病，包括伤口愈合、关节炎、骨质疏松症和肌肉萎缩疾病，影响着全球数百万人。如果能够克服现有的障碍，从现成的、与患者匹配的干细胞中有效地衍生出中胚层组织，这些疾病就可以用基于干细胞的再生医学来治疗。不幸的是，胚胎干细胞（ESC）和诱导多能干细胞（IPSC）的中胚层定向分化目前仅限于心血管和血液衍生物。肌肉、软骨和结缔组织分化的可复制方案，或者更具体地说，那些仅由体前中胚层（PSM）产生的中胚层衍生物尚未出现。虽然有可能从人类ESC中获得后中胚层的某些细胞类型，但在这些组织的再生程序可行之前，这些效率（通常<1%）必须大大提高。先前的研究表明，内源性psm -祖细胞（PSM-Pr）位于原始条纹和Hensen's结的边界（PSM-Pr生态位）。PSM-Pr的后代在近轴中胚层定植并产生体，体又产生胚胎的骨骼肌、软骨和结缔组织。这里描述的工作的主要焦点是识别和详尽地描述组成和维持内源性祖干细胞及其生态位的细胞类型。在这个项目中，我们将(1)识别位于边界的所有细胞类型