Hox-Expressing Stromal Cells in Muscle Development and Repair

摘要 肌肉骨骼发育、修复和再生的一个基本问题是如何 间充质干细胞/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基因仅在祖细胞丰富的骨骼中表达 骨髓间充质干细胞/基质细胞和Hox11基因的表达仅限于 斑足类肢体区域(桡骨/尺骨；胫骨/腓骨)。HOX功能丧失导致骨修复缺陷 成人以及先前发现的胚胎骨骼中的缺陷(Rux等人，在出版社中， 发育细胞)。我们之前也已经证明了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，并在发育阶段发挥作用 来设计四肢肌肉的图案。新的初步数据显示，肌肉间质表达 在成人期持续，并随着肌肉损伤而扩大，与持续 在成人肌肉组织中的功能。我们已经产生了一个Hoxd11条件等位基因，它将允许我们 有选择地在出生后或成年阶段移除Hox11功能，并在成年时检查持续功能 各阶段。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-MSCs)对于正确的发育模式(AS)是重要的 以及骨骼的修复)，这两个细胞群体都表现出区域特异性。我们的Hoxa11eGFP 敲门记者让我们探索这两种生物在生物学上的相似和差异 发育阶段和损伤期间的基质种群以及对照和突变体之间的差异 修复/再生。这项研究的目的是研究hox基因在肌肉中的持续作用。 间质细胞及其调控的信号通路的性质 开发和修复。这些分析的成功结果将展示一种新的功能 为HOX基因在成人肌肉修复中的作用提供了关键的新信息 结缔组织基质细胞对肌肉发育和修复过程的调控及其如何 基质祖细胞与更具特征的骨骼间充质干细胞相比较。通过以下方式生成的数据 这项研究将为在肌肉和间充质干细胞这一重要方面继续提供资金提供基础 生物学。

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.