Hox genes regulate functionally distinct, regionally restricted MSC populations

Hox 基因调节功能不同、区域受限的 MSC 群体

• 批准号: 10197314
• 负责人: Deneen M Wellik
• 金额: $ 40.35万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197314
• 关键词: Address; Adipose tissue; Adult; Alleles; Animals; Biological; Biological Assay; Bone Marrow; CRISPR/Cas technology; Cartilage; Cell Differentiation process; Cell Surface Receptors; Cell physiology; Cells; Characteristics; Clinical Engineering; Defect; Development; Elements; Embryonic Development; Engineering; Environment; Exons; Expression Profiling; Fracture; Gene Expression; Genes; Genetic; Goals; Growth; Hematopoietic stem cells; Home environment; Homeobox Genes; In Vitro; Knowledge; Label; Laboratories; Lead; Life; Limb structure; Maintenance; Measures; Mediating; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Morphology; Musculoskeletal; Musculoskeletal Development; Mutant Strains Mice; Natural regeneration; Outcome; Pattern; Performance; Phase; Platelet-Derived Growth Factor alpha Receptor; Population; Radial; Regenerative Medicine; Reporter; Reporting; Research; Role; Skeleton; Source; Specificity; Sternum; Stromal Cells; Testing; Tissue Engineering; Tissues; Transplantation; Work; bone; bone marrow stromal stem cell; cell behavior; cell type; clinical application; fibula; gene function; gene replacement; genetic approach; genome editing; in vitro Assay; in vivo; in vivo evaluation; mesenchymal stromal cell; mutant; paralogous gene; postnatal; product development; progenitor; prospective; regenerative; regenerative therapy; repaired; rib bone structure; skeletal; stem; stem cells; tibia; transcription factor; ulna

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.

摘要 多能间充质干细胞/基质细胞（MSC）被用于大量的造血干细胞。 再生/修复临床应用和组织工程方法。平移 在各种情况下使用这些细胞的结果差异很大， 既有功能又能在体内适当整合的肌肉骨骼组织 一个重大的挑战。最近几个实验室的研究已经完善和推进了 领域的能力，以丰富的间充质干细胞/基质细胞具有高祖细胞的潜力，但最近的研究 从我的实验室发现，从成人不同骨骼的骨髓中提取的MSC 骨架保持区域限制的，独特的Hox表达谱， 在发育过程中（Rux，et al.，Dev. Cell，2016）。Hox的表达仅在 富集祖细胞的MSC群体（PDGFRα+/CD 51+，LepR-Cre标记）， 在分化的骨骼细胞类型或非祖细胞富集的（LepR阴性）非 内皮基质。此外，骨折修复研究表明，Hox 11基因的功能， 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 Hox 11功能的丧失导致MSC祖细胞无法向软骨分化， 骨（但对脂肪分化没有影响）。这就引出了一个更广泛的问题， MSC中独特的Hox表达模式是否是发育和功能的副产品 通过发育模式化阶段后的共同机制， 潜力另一种更有趣、更有生物学意义的可能性是， 独特的Hox基因或旁系同源物可以在空间上不同的MSC中差异地起作用， 区域特定的调控信息在生长，维护和修复，通过成人 阶段这对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 和再生方法作为MSC的独特功能和调节特征 可能会因其来源而有很大不同;这可能会深刻影响其 在临床和组织工程应用中的性能。