Directing the Fate of Cells to Myogenic Lineages

将细胞的命运引导至肌源性谱系

• 批准号: 7555208
• 负责人: MINDY GEORGE-WEINSTEIN
• 金额: $ 27.63万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7555208
• 关键词: Ablation; Adult; Biological Models; Bone Morphogenetic Proteins; Cadherins; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cell Differentiation process; Cell-Cell Adhesion; Cells; Chick Embryo; Coculture Techniques; Commit; Communication; Condition; Contractile Proteins; Developmental Biology; Down-Regulation; E-Cadherin; Embryo; Ensure; Environment; Epiblast; Event; Excision; Family member; Immunofluorescence Immunologic; In Vitro; Label; Lead; Light; Mediating; Mesoderm; Messenger RNA; Monitor; Muscle; Muscle satellite cell; Myocardium; N-Cadherin; Natural regeneration; Organ; Pathway interactions; Play; Pluripotent Stem Cells; Primitive Streaks; Principal Investigator; Process; Publishing; Recruitment Activity; Regenerative Medicine; Research; Research Design; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Skeletal Development; Skeletal Muscle; Skeletal system; Somites; Specific qualifier value; Staging; Stem cells; Striated Muscles; Testing; Therapeutic; Tissues; Western Blotting; Work; base; conditioning; design; desire; embryo tissue; embryonic stem cell; implantation; in vivo; inhibitor/antagonist; member; method development; myogenesis; novel; osteogenin; repaired; research study; response; tissue regeneration; transcription factor

Cell-based regenerative medicine is a natural extension of developmental biology. Embryonic stem cells (ES cells) give rise to the entire embryo and have the potential to repair diseased tissues in the adult. Cell differentiation is preceded by specification, a process that restricts these pluripotent cells to a particular lineage. Tissue regeneration is dependent on the availability of factors that specify stem cells to the desired lineage and promote their differentiation. Given that the environment of diseased tissues is unlikely to be the same as that of the developing embryo, stem cells may require "conditioning" prior to or during implantation. The overall hypotheses guiding the proposed research are: (1) the fate of pluripotent stem cells can be directed in vitro and in vivo by stem cells previously committed to a particular lineage, and (2) the induction process is mediated by a combination of soluble factors and cell-cell adhesions. This project builds on our published observations that chick epiblast cells expressing MyoD mRNA in vivo recruit pluripotent epiblast cells to the skeletal muscle lineage in vitro by releasing a factor(s) that inhibits the bone morphogenetic protein (BMP) signaling pathway and promotes the expression of N-cadherin. In the absence of MyoD positive epiblast cells, more pluripotent cells form cardiac muscle. A key event in muscle differentiation is the downregulation of E-cadherin. Preliminary studies demonstrate that ablation of MyoD positive cells in the epiblast results in herniation of the organs through the ventral body wall and a reduction in skeletal muscle in the somites. The proposed studies are designed to explore the mechanism whereby MyoD positive epiblast cells promote skeletal myogenesis in the somites in vivo, and to identify the factors that regulate cadherin switching and recruitment of cells to the skeletal and cardiac muscle lineages in vitro. The experiments will focus on the roles of Wnt, 7GF-/3, BMP, and BMP inhibitor family members in these processes. The proposed studies may reveal a novel mechanism for regulating skeletal myogenesis in vivo, and lead to the development of methods for conditioning stem cells to ensure that they are biased to differentiate along the desired pathway and express the appropriate cell-cell adhesion proteins prior to their implantation into diseased tissues.

基于细胞的再生医学是发育生物学的自然扩展。胚胎茎 细胞（ES细胞）产生整个胚胎，并有可能修复患病的组织 成人。细胞分化之前是规格，该过程限制了这些多能 细胞到特定的谱系。组织再生取决于因素的可用性 将干细胞指定为所需的谱系并促进其分化。鉴于那个 患病组织的环境不太可能与发育中的胚胎的环境相同 细胞可能需要在植入之前或植入过程中“调理”。总体假设指导 拟议的研究是：（1）多能干细胞的命运可以在体外和体内定向 干细胞先前致力于特定谱系，（2）诱导过程是由 可溶性因子和细胞粘附的组合。这个项目建立在我们已发布的 观察到表达Myod mRNA的雏鸡在体内募集多脂蛋白的表达多能细胞 细胞通过释放抑制骨骼的因子，在体外进入骨骼肌谱系 形态发生蛋白（BMP）信号通路并促进N-钙粘蛋白的表达。在 没有Myod阳性e型细胞，更多的多能细胞会形成心肌。一个关键事件 肌肉分化是E-钙粘蛋白的下调。初步研究表明 肉体中的Myod阳性细胞在纤维细胞中的消融导致器官通过腹侧疝 体壁和体骨骼肌肉减少。拟议的研究旨在 探索Myod阳性一个阳性细胞促进骨骼肌发生的机制 体内体体，并确定调节钙粘蛋白切换和募集细胞的因素 在体外到骨骼和心肌谱系。实验将集中于Wnt的角色， 在这些过程中，7GF-/3，BMP和BMP抑制剂家族成员。拟议的研究可能 揭示了调节体内骨骼肌发生的新型机制，并导致发育 调节干细胞的方法，以确保它们有偏见沿着 所需的途径并在植入之前表达适当的细胞粘附蛋白 进入患病的组织。