Hox genes regulate functionally distinct, regionally restricted MSC populations

摘要 多潜能间充质干细胞/基质细胞(MSCs)被大量用于 再生/修复临床应用和组织工程方法。翻译 这些细胞在不同环境中的使用结果差异很大，并产生了新的 保留了既有功能又能在体内适当整合的肌肉骨骼组织 这是一个重大的挑战。来自几个实验室的最新研究提炼和推进了 菲尔德对具有高祖细胞潜能的MSCs/基质细胞的富集力，但最近的一项研究 从我的实验室发现，来自成人不同骨骼的骨髓间充质干细胞 骨架维护已建立的区域受限的、唯一的Hox表达简档 在开发期间(Rux等人，开发人员CELL，2016)。仅观察到HOX表达 祖细胞富集型间充质干细胞群体(PDGFRα/CD51Lepr-Cre标记) 在分化的骨骼细胞类型或非祖细胞富集型(Lepr阴性)非 内皮间质。此外，骨折修复研究表明，Hox11基因在 成年间充质干细胞种群和丢失的中央肢体区域(斑足类：桡骨/尺骨，胫骨/腓骨) Hox11功能缺失导致MSC前体细胞不能分化为软骨和 骨骼(但对脂肪分化没有影响)。这就引出了一个更广泛的问题 MSCs中独特的HOX表达模式是否是发育和功能的副产品 通过发育模式化阶段后的共同机制促进一般MSC 潜力。或者，更有趣、更有生物学意义的可能性是 独特的HOX基因或平行基因可能在空间上不同的MSCs中发挥不同的功能，以提供 成年后生长、维持和修复过程中特定区域的调控信息 各阶段。这对骨髓间充质干细胞在肌肉骨骼组织工程中的应用具有重要意义 作为MSCs独特的功能和调节特性的再生途径 可能会有很大的差异，这取决于它们的来源；这可能会对它们的 在临床和组织工程应用中的表现。

ABSTRACT Multipotent mesenchymal stem/stromal cells (MSCs) are used in a large number of regenerative/reparative clinical applications and tissue engineering approaches. Translational outcomes from the use of these cells in various contexts vary widely and generating new musculoskeletal tissue that is both functional and able to integrate appropriately in vivo remains a major challenge. Recent research from several laboratories have refined and advanced the field's ability to enrich for MSCs/stromal cells with high progenitor potential, but a recent study from my laboratory reveals that MSCs from the bone marrow of different bones of the adult skeleton maintain the regionally restricted, unique Hox expression profile that is established during development (Rux, et al., Dev. Cell, 2016). Hox expression is only observed in progenitor-enriched MSC populations (PDGFRα+/CD51+, LepR-Cre labeled) and is not detected in differentiated skeletal cell types or in non-progenitor enriched (LepR-negative) non- endothelial stroma. Further, fracture repair studies demonstrate that Hox11 genes function in the central limb regions (zeugopod: radius/ulna, tibia/fibula) in adult MSC populations and loss of Hox11 function leads to the inability of MSC progenitors to differentiate towards cartilage and bone (but has no effect on adipose differentiation). This leads to the broader question of whether unique Hox expression patterns in MSCs are a by-product of development and function via a common mechanism after developmental patterning stages to promote general MSC potential. Alternatively, the much more interesting and biologically significant possibility is that unique Hox genes or paralogs may function differentially in spatially distinct MSCs to provide region-specific regulatory information during growth, maintenance and repair through adult stages. This has critical implications for the use of MSCs in musculoskeletal tissue engineering and regenerative approaches as the unique functional and regulatory characteristics of MSCs may differ considerably depending on their origin; this could profoundly impact their performance in clinical and tissue engineering applications.