Hox-Expressing Stromal Cells in Muscle Development and Repair

表达 Hox 的基质细胞在肌肉发育和修复中的作用

• 批准号: 9530540
• 负责人: Deneen M Wellik
• 金额: $ 6.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9530540
• 关键词: Adult; Alleles; Behavior; Biological; Bone Marrow; Bone Regeneration; Cell physiology; Cell surface; Cells; Cellular biology; Connective Tissue; Data; Defect; Development; Dissection; Embryo; Embryonic Development; Flow Cytometry; Fracture; Funding; Future; Gene Expression; Gene Expression Profiling; Generations; Genes; Goals; Homeobox Genes; In Vitro; Injury; Knock-in; Knowledge; Laboratories; Limb structure; Mammals; Mesenchymal; Modeling; Molecular; Mus; Muscle; Muscle Development; Musculoskeletal; Musculoskeletal Development; Musculoskeletal System; Natural regeneration; Nature; Outcome; Pathway interactions; Pattern; Platelet-Derived Growth Factor alpha Receptor; Population; Process; Property; Publishing; Radial; Regenerative Medicine; Regulation; Reporter; Reporting; Role; Signal Pathway; Skeletal bone; Skeleton; Specificity; Stem cells; Stromal Cells; Testing; Tissue Engineering; Tissues; barium chloride; bone; cell type; fibula; gene function; injury and repair; insight; interest; mutant; novel; osteogenic; postnatal; progenitor; repaired; response; skeletal; skeletal tissue; stem; stromal progenitor; stromal progenitor population; tibia; tool; ulna

ABSTRACT A fundamental question in musculoskeletal development, repair and regeneration is how mesenchymal stem/stromal cells regulate development and repair processes. Our recently published data shows that, in the skeleton, Hox genes are exclusively expressed in progenitor-enriched, bone marrow mesenchymal stem/stromal cells (BM-MSCs) and Hox11 gene expression is confined to the zeugopod limb region (radius/ulna; tibia/fibula). Loss of Hox function leads to defects in bone repair in adults as well as previously identified defects in the embryonic skeleton (Rux, et al, in press, Developmental Cell). We have also previously shown that Hox11 genes are expressed in muscle connective tissue stromal cells with the same regional restriction, and function at developmental stages to pattern the muscles of the limb. New preliminary data shows that muscle stromal expression continues through adult stages and expands in response to muscle injury, consistent with continued function in adult muscle tissue. We have generated a Hoxd11 conditional allele that will allow us to selectively remove Hox11 function at postnatal or adult stages and examine continued function at adult stages. In both the skeletal and muscle tissue, Hox genes are expressed only in the stromal progenitor cells (BM-MSCs in the skeleton) that are known to be important for proper developmental patterning (as well as repair in the skeleton) and both cell populations show regional specificity. Our Hoxa11eGFP knock-in reporter allows us to probe the biological similarities and differences between these two stromal populations as well as between controls and mutants at developmental stages and during injury repair/regeneration. The goal of this study is to investigate the continued role for Hox genes in muscle stromal cells and the nature of the signaling pathways regulated in muscle stromal cells during development and repair. A successful outcome from these analyses will demonstrate a novel function for Hox genes in adult muscle repair and will provide critical new information regarding the nature of connective tissue stromal cell regulation of muscle development and repair processes and how these stromal progenitors compare to more well-characterized skeletal MSCs. The data generated through this study will provide the basis for continued funding on this important aspect of muscle and MSC biology.

抽象的 肌肉骨骼发育，修复和再生的一个基本问题是 间充质干/基质细胞调节发育和修复过程。我们最近出版的 数据表明，在骨骼中，HOX基因专门以祖细胞增强的骨头表达 骨髓间充质干/基质细胞（BM-MSC）和HOX11基因表达仅限于 Zeugopod肢体区域（半径/尺骨；胫骨/腓骨）。 HOX功能的丧失导致骨修复缺陷 成年人以及先前发现的胚胎骨骼缺陷 发育单元格）。我们以前还表明HOX11基因在肌肉中表达 结缔组织基质细胞具有相同的区域限制，并且在发育阶段的功能 对肢体的肌肉进行图案。新的初步数据表明肌肉基质表达 继续通过成人阶段并响应肌肉损伤而扩展，与继续 在成年肌肉组织中的功能。我们已经产生了一个有条件的等位基因，这将使我们能够 在产后或成人阶段有选择地删除HOX11功能，并检查成人的持续功能 阶段。在骨骼和肌肉组织中，HOX基因仅在基质祖细胞中表达 细胞（骨骼中的BM-MSC）对于适当的发育模式很重要（AS AS 以及骨骼的修复）和两个细胞种群都显示出区域特异性。我们的Hoxa11EGFP 敲门记者使我们能够探究这两者之间的生物学相似性和差异 在发育阶段和受伤期间，基质种群以及对照组和突变体之间 维修/再生。这项研究的目的是研究HOX基因在肌肉中的持续作用 基质细胞和在肌肉基质细胞中调节的信号通路的性质 开发和维修。这些分析的成功结果将证明一个新的功能 对于成人肌肉修复中的HOX基因，将提供有关性质的关键新信息 结缔组织基质细胞调节肌肉发育和修复过程以及如何 基质祖细胞与更良好的骨骼MSC相比。通过 这项研究将为肌肉和MSC的这一重要方面的持续资助提供基础 生物学。