Bone is a renewable tissue that is constantly remodeled throughout life and has the ability to self-repair following an injury or disease-related bone loss. As the appropriate recruitment of skeletal stem cells (SSCs)/progenitors is required for successful bone homeostasis and repair, targeting stem cells/progenitors offers an innovative therapeutic strategy against skeletal pathologies. Although SSCs can be isolated from many tissues and share common genetic markers, recent studies demonstrated the cellular characteristics and contributions of different SSC populations are distinct. Less is known about what factors contribute to this diversity and how they influence SSC populations that reside in different locations. In addition, while there are many orthopedic conditions where muscle plays a vital role in tissue regeneration and disease progression, the role of muscle resident SSC in bone repair remains largely elusive.
Published work and our studies showed that the paired related homeobox gene1 (Prx1) expressing cells connote postnatal SSCs that contribute to bone homeostasis and tissue repair. In this study, we hypothesize that intrinsic regulation and environmental factors work in concert to generate the diversity of Prx1 cell populations. To investigate the effect of external and internal regulations, we first established an efficient sponge transplantation model. This model successfully recruited and relocated local cells, including Prx1+ cells. Bone Morphogenetic Protein 2 (BMP2) was used to demonstrate the ability of Prx1+ cells to form bone. Our data revealed the muscle environment was not permissive for bone formation under homeostasis, while the periosteum created a supportive niche for skeletal stem cells to participate in bone remodeling and maintenance. Unlike periosteal cells, which were prone to skeletogenesis, muscle-derived Prx1+ cells were regulated by an intrinsic regulatory mechanism allowing for an osteogenic capacity but requiring specific stimulation(s), including high amount of BMP2 and bone injury. To further illustrate the heterogeneity of Prx1 cell populations, subpopulations P1 (CD105-CD200+), P2(CD105-CD200-), and P3 (CD105+) from bone marrow, periosteum and muscle were analyzed by bulk RNA sequencing. Results showed P2/P3 from bone marrow and periosteum were relatively active, while all muscle resident Prx1+ cells were quiescent under homeostatic conditions but could quickly re-enter the cell cycle upon external stimulation. Single-cell RNA sequencing analyses on SSCs also confirmed the quick activation and differentiation of muscle-derived SSCs on post-operative Day (POD) 3.
In conclusion, this study elucidates the diversity of a mesenchymal cell population marked by Prx1 expression, which is generated by the interaction between intrinsic regulation of stem cells and external tissue environments. Our data demonstrated that SSC activation under physiological or pathological conditions (ectopic bone formation and injury) is site-specific, making muscle derived SSC a potential target for skeletal repair and bone disorders. / 2025-11-02T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/47443 |
| Date | 03 November 2023 |
| Creators | Liu, Yu |
| Contributors | Bragdon, Beth |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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