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Identification of LRP1 and CD13 expressing human periosteal cells for stem cell-mediated bone repair

ABSTRACT: Human periosteal skeletal stem cells (P-SSCs) are critical for cortical bone maintenance and repair. However, their in vivo identity, molecular characteristics, and specific markers remain unknown. Here, single-cell sequencing revealed human periosteum contains SSC clusters expressing known SSC markers, PDPN and PDGFRA. Notably, human P-SSCs, but not bone marrow SSCs (BM-SSCs), selectively expressed newly identified markers, LRP1 and CD13. Single-cell analysis of mouse periosteum further supported the preferential expression of LRP1 and CD13 in Prx1 P-SSCs. These LRP1CD13 human P-SSCs were perivascular cells with high osteochondrogenic but minimal adipogenic potential. In addition, LRP1CD13 human P-SSCs are maintained in vitro and self-renew in vivo upon transplantation into bone injuries in mice. When Lrp1 was conditionally deleted in Prx1-lineage cells, it led to severe bone deformity, short statue, and periosteal defects. By contrast, local treatment with a LRP1 agonist at the injury sites induced early P-SSC proliferation and bone healing. Thus, human periosteum contains unique osteochondrogenic stem cell subsets, and these P-SSCs express specific markers, LRP1 and CD13, with regulatory mechanism through LRP1 that enhances P-SSC function and bone repair.

ORGANISM(S): Mus musculus

PROVIDER: GSE276574 | GEO | 2024/11/04

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.

Project description:Glycolytic metabolism, once considered merely a consequence of cellular function, has emerged as a crucial regulator of cellular differentiation. Both glycolysis and oxidative phosphorylation (OXPhos) are vital for osteoblastogenesis. Osteoblasts are the cells that make bone. To deepen our understanding of OXPhos's role in bone mass accrual, we engineered a mutant mouse model deficient in Mitochondrial Transcription Factor A (TFAM) specifically in mesenchymal progenitors within the limb bud and their descendants, using the PRX1-Cre driver system. TFAM is essential for transcription of the mitochondrial genes that encode critical components of the electron transport chain, thereby governing OXPhos. Our TFAM mutant mice exhibit marked shortening of long bones, evident at birth and progressing with age, accompanied by growth plate abnormalities and bone deformities. Critically, these mice develop spontaneous fractures in long bone mid-shafts by three weeks of age, indicating significant compromise in bone integrity. Comparative analyses using MicroCT and histomorphometry reveal drastic cortical bone thinning in mutants due to severely impaired osteoid deposition and bone formation, especially in the diaphyseal periosteum. Furthermore, an increased number of osteoclasts at this site suggests that an elevated bone resorption contributes to the phenotype. Acknowledging the active role of energy metabolism in cell differentiation and function, we measured ATP production in PRX1 lineage periosteal cells. TFAM deletion led to a substantial decrease in steady-state intracellular ATP levels, highlighting a critical metabolic deficit. To rectify this metabolic defect and potentially correct the resultant phenotype, we bred TFAM mice with another mouse line expressing mutated, oxygen-independent Hypoxia Inducible Factor 1alpha (HIF1dPA) within PRX1 lineage cells (yielding TFAM/HIF1dPA mice). These double mutants did not experience spontaneous fractures, and their cortical bone thickness and the ability of periosteal cells to accumulate osteoid was fully restored. Therefore, by examining the transcriptional profile of periosteal cells, our aim is to determine whether TFAM deficiency alters their genetic landscape and if HIF1 activation can reverse these changes. Our goal is to provide new insights into the role of energy metabolism in shaping the transcriptome landscape, thereby influencing cell differentiation and activity.

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Identification of LRP1 and CD13 expressing human periosteal cells for stem cell-mediated bone repair

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