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.

摘要 肌肉骨骼发育、修复和再生中的一个基本问题是， 间充质干/基质细胞调节发育和修复过程。我们最近出版的 数据显示，在骨骼中，Hox基因仅在祖细胞富集的骨中表达， 骨髓间充质干/基质细胞（BM-MSCs）和Hox 11基因表达仅限于 齐足动物肢体区域（桡骨/尺骨;胫骨/腓骨）。Hox功能丧失导致骨修复缺陷， 成年人以及先前鉴定的胚胎骨骼缺陷（Rux，等，出版中， 发育细胞）。我们以前也表明Hox 11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，并在发育阶段发挥作用 来模拟肢体的肌肉新的初步数据显示，肌肉基质表达 持续通过成人阶段，并扩大对肌肉损伤的反应，符合持续 在成人肌肉组织中发挥作用。我们已经产生了一个Hoxd 11条件等位基因，这将使我们能够 在出生后或成年阶段选择性地去除Hox 11功能，并在成年时检查持续的功能 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），已知其对适当的发育模式（如 以及骨骼中的修复），并且两种细胞群都显示出区域特异性。我们的Hoxa 11 eGFP 敲入报告基因使我们能够探测这两者之间的生物学相似性和差异 基质群体以及发育阶段和损伤期间对照和突变体之间的差异 修复/再生。本研究的目的是研究Hox基因在肌肉中的持续作用， 间质细胞和肌肉间质细胞中调节的信号通路的性质 发展和修复。这些分析的成功结果将证明一种新的功能 Hox基因在成人肌肉修复中的作用，并将提供关于 结缔组织基质细胞调节肌肉发育和修复过程，以及这些 基质祖细胞与更好表征的骨骼MSC相比。通过以下方式生成的数据 这项研究将为继续资助肌肉和MSC的这一重要方面提供基础 生物学