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Discovery of neuro- and vascular-associated periosteum-resident macrophages essential for cortical bone regeneration [veh vs pos]

ABSTRACT: The periosteum contains a highly osteogenic and neuro-vascular microenvironment that is essential for cortical bone formation and regeneration. Resident tissue macrophages (RTMs) are critical for maintaining tissue-specific niches and participating in tissue regeneration. However, the characteristics, origin and functions of periosteum-resident macrophages (PRMs) remain largely unknown. In this study, we demonstrated that PRMs are generated during embryonic hematopoiesis and are self-maintained locally during regeneration. Furthermore, by single-cell RNA sequencing analysis of periosteum myeloid cells, CX3CR1+CD45+ACE+ and CX3CR1+CD45+CD74+ cells were identified as vascular-associated and neuro-associated PRMs, respectively. Both cell types were found to arise from CX3CR1+CD168+CD45+ PRMs and shown to play critical roles in maintaining the periosteum neuro-vascular niche and promoting early-stage cortical bone regeneration. Importantly, the neuro-vascular characteristic of PRMs are directly modulated via Periostin, the essential ECM distributed in periosteum. These findings elucidate the characteristics and origins of PRMs and reveal their essential roles in maintaining the local niche and cortical bone regeneration as well as highlighting the potential value of PRMs as a therapeutic target in bone regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE190478 | GEO | 2024/06/01

REPOSITORIES: GEO

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Project description:The expression of Prx1 has been used as a marker to define the skeletal stem cells (SSC) populations found within the bone marrow and periosteum that contribute to bone regeneration. However, Prx1 expressing SSCs (Prx1-SSCs) are not restricted to the bone compartments, but are also located within the muscle and able to contribute to ectopic bone formation. Little is known however, about the mechanism(s) regulating Prx1-SSCs that reside in muscle and how they participate in bone regeneration. This study compared both the intrinsic and extrinsic factors of the periosteum and muscle derived Prx1-SSCs and analyzed their regulatory mechanisms of activation, proliferation, and skeletal differentiation. There was considerable transcriptomic heterogeneity in the Prx1-SSCs found in muscle or the periosteum however in vitro cells from both tissues show tri-lineage (adipose, cartilage and bone) differentiation. At homeostasis, periosteal derived Prx1 cells were proliferative and low levels of BMP2 were able to promote their differentiation, while the muscle derived Prx1 cells were quiescent and refractory to comparable levels of BMP2 that promoted periosteal cell differentiation. The transplantation of Prx1-SCC from muscle and periosteum into either the same site from which they were isolated, or their reciprocal sites showed that periosteal cell transplanted onto the surface of bone tissues differentiated into bone and cartilage cells but was incapable of similar differentiation when transplanted into muscle. Prx1-SSCs from the muscle showed no ability to differentiate at either site of transplantation. Both fracture and ten times the BMP2 dose was needed to promote muscle-derived cells to rapidly enter the cell cycle as well as undergo skeletal cell differentiation. This study elucidates the diversity of the Prx1-SSC population showing that cells within different tissue sites are intrinsically different. While muscle tissue must have factors that promote Prx1-SSC to remain quiescent, either bone injury or high levels of BMP2 can activate these cells to both proliferate and undergo skeletal cell differentiation. Finally, these studies raise the possibility that muscle SSCs are potential target for skeletal repair and bone diseases.

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Discovery of neuro- and vascular-associated periosteum-resident macrophages essential for cortical bone regeneration [veh vs pos]

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