Hox genes regulate functionally distinct, regionally restricted MSC populations

摘要 多能间充质干细胞/基质细胞（MSC）被广泛用于 再生/修复临床应用和组织工程方法。翻译性 在不同情况下使用这些细胞的结果差异很大，并产生新的 具有功能性且能够在体内适当整合的肌肉骨骼组织仍然存在 一个重大挑战。几个实验室的最新研究完善并推进了 领域富集具有高祖细胞潜力的 MSC/基质细胞的能力，但最近的一项研究 我的实验室揭示了来自成人不同骨骼骨髓的间充质干细胞 骨架维持已建立的区域限制的、独特的 Hox 表达谱 开发期间（Rux 等人，Dev. Cell，2016）。 Hox 表达仅在 富含祖细胞的 MSC 群体（PDGFRα /CD51，LepR-Cre 标记），并且不是 在分化的骨骼细胞类型或非祖细胞富集（LepR 阴性）非 内皮基质。此外，骨折修复研究表明 Hox11 基因在 成年 MSC 群体中的中央肢体区域（zeugopod：桡骨/尺骨、胫骨/腓骨）和损失 Hox11 功能的丧失导致 MSC 祖细胞无法分化为软骨和 骨（但对脂肪分化没有影响）。这导致了更广泛的问题 MSC 中独特的 Hox 表达模式是否是发育和功能的副产品 通过发育模式阶段后的共同机制促进一般 MSC 潜力。或者，更有趣且具有生物学意义的可能性是 独特的 Hox 基因或旁系同源物可能在空间不同的 MSC 中发挥不同的功能，以提供 成人生长、维护和修复过程中特定区域的监管信息 阶段。这对于 MSC 在肌肉骨骼组织工程中的应用具有重要意义 和再生方法作为间充质干细胞独特的功能和调节特征 取决于其来源，可能会有很大差异；这可能会对他们产生深远的影响 临床和组织工程应用中的性能。

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.