Abstract:Currently, there is no consensus whether there is a single or multiple postnatal stem cell population(s) that contribute to skeletal homeostasis and postnatal bone formation. A known population of cells that express Prx1 contributes to postnatal bone formation. Prx1 expression also connotes calvaria and appendicular tissues during embryonic development. A transgenic tamoxifen inducible Prx1 reporter mouse was used for lineage tracking, to characterize the postnatal contribution of Prx1 expressing cells in skel… Show more
“…Within the nonhematopoietic population isolated from the muscle, periosteum and bone marrow, the percentage of Prx1 cells were 33.22 ± 9.70%, 5.58 ± 1.70%, and 0.58 ± 0.13% (Figure 4B). Overall, Prx1-expressing cells have the highest fraction in skeletal muscle, which aligns with the observations we obtained from our previous histological analysis (Bragdon et al, 2022).…”
Section: Molecular Profiling Of the Prx1 Cells From Different Skeleta...supporting
confidence: 92%
“…Advances with genetic mouse models have revealed several markers that can be used to define various populations of SSCs, including Nestin, LepR, Mx1, αSMA, Periostin, Cathespin K, Cxcl12, Prx1 (Méndez-Ferrer et al, 2010;Park et al, 2012;Greenbaum et al, 2013;Zhou et al, 2014;Debnath et al, 2018;Duchamp de Lageneste et al, 2018). Published work along with our studies showed Prx1 expressing cells connote a multi-potential postnatal SSC population that retained its embryonic tissue specification, localized to multiple sites such as bone marrow, periosteum, and muscle within the appendicular regions and contributes to homeostatic maintenance, fracture repair, and HO (Batista et al, 2019;Julien et al, 2021;Bragdon et al, 2022).…”
Section: Introductionmentioning
confidence: 62%
“…This overexpression is observed in all three tissues where bone marrow shows the most significant difference while muscle to a much less extent. It implies that muscle-derived skeletal stem/progenitor cells do not demonstrate osteogenic capacity under homeostasis unless they receive environmental signals, where bone marrow and periosteum counterparts are constantly turned over at a higher rate and involved in homeostatic maintenance of the bone tissue as previously suggested (Park et al, 2012;Bragdon et al, 2022).…”
Section: Discussionmentioning
confidence: 88%
“…The wild type C57BL/6J (B6, Jackson Laboratory, Stock 000,664) and transgenic mice, Prx1-CreER/Ai14/Rag1, were used for this study. The Prx1-CreER/Ai14/Rag1 mice was previously described ( Bragdon et al, 2022 ), briefly the strain was established by crossing the Ai14 (007,914, B6. Cg-Gt (ROSA)26Sor tm14(CAG-tdTomato)Hze /J), with Prx1-Cre/ERT2-EGFP (provided by Dr. Shunichi Murakami ( Kawanami et al, 2009 )) and with the Rag1 (002,216, B6.129S7-Rag1 tm1/MOM /J).…”
The expression of Prx1 has been used as a marker to define the skeletal stem cells (SSCs) 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 showed 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.
“…Within the nonhematopoietic population isolated from the muscle, periosteum and bone marrow, the percentage of Prx1 cells were 33.22 ± 9.70%, 5.58 ± 1.70%, and 0.58 ± 0.13% (Figure 4B). Overall, Prx1-expressing cells have the highest fraction in skeletal muscle, which aligns with the observations we obtained from our previous histological analysis (Bragdon et al, 2022).…”
Section: Molecular Profiling Of the Prx1 Cells From Different Skeleta...supporting
confidence: 92%
“…Advances with genetic mouse models have revealed several markers that can be used to define various populations of SSCs, including Nestin, LepR, Mx1, αSMA, Periostin, Cathespin K, Cxcl12, Prx1 (Méndez-Ferrer et al, 2010;Park et al, 2012;Greenbaum et al, 2013;Zhou et al, 2014;Debnath et al, 2018;Duchamp de Lageneste et al, 2018). Published work along with our studies showed Prx1 expressing cells connote a multi-potential postnatal SSC population that retained its embryonic tissue specification, localized to multiple sites such as bone marrow, periosteum, and muscle within the appendicular regions and contributes to homeostatic maintenance, fracture repair, and HO (Batista et al, 2019;Julien et al, 2021;Bragdon et al, 2022).…”
Section: Introductionmentioning
confidence: 62%
“…This overexpression is observed in all three tissues where bone marrow shows the most significant difference while muscle to a much less extent. It implies that muscle-derived skeletal stem/progenitor cells do not demonstrate osteogenic capacity under homeostasis unless they receive environmental signals, where bone marrow and periosteum counterparts are constantly turned over at a higher rate and involved in homeostatic maintenance of the bone tissue as previously suggested (Park et al, 2012;Bragdon et al, 2022).…”
Section: Discussionmentioning
confidence: 88%
“…The wild type C57BL/6J (B6, Jackson Laboratory, Stock 000,664) and transgenic mice, Prx1-CreER/Ai14/Rag1, were used for this study. The Prx1-CreER/Ai14/Rag1 mice was previously described ( Bragdon et al, 2022 ), briefly the strain was established by crossing the Ai14 (007,914, B6. Cg-Gt (ROSA)26Sor tm14(CAG-tdTomato)Hze /J), with Prx1-Cre/ERT2-EGFP (provided by Dr. Shunichi Murakami ( Kawanami et al, 2009 )) and with the Rag1 (002,216, B6.129S7-Rag1 tm1/MOM /J).…”
The expression of Prx1 has been used as a marker to define the skeletal stem cells (SSCs) 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 showed 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.
“…Consistently, most Prx1 + SSPCs are present in the long bone periosteum during embryonic and postnatal development. Prx1 + cells are present during embryonic development restricted to the mesoderm which becomes mesenchymal cells postnatally without losing their embryonic tissue specification and thus have SSPC properties (Du et al, 2013;Bragdon et al, 2022). These pnPrx1 + P-SSPCs are known to inhibit adipogenesis by activating TGFβ signaling (Du et al, 2013).…”
Section: Unique Regulation Of Periosteal Sspcs (P-sspcs)mentioning
Skeletal stem/progenitor cells (SSPCs), characterized by self-renewal and multipotency, are essential for skeletal development, bone remodeling, and bone repair. These cells have traditionally been known to reside within the bone marrow, but recent studies have identified the presence of distinct SSPC populations in other skeletal compartments such as the growth plate, periosteum, and calvarial sutures. Differences in the cellular and matrix environment of distinct SSPC populations are believed to regulate their stemness and to direct their roles at different stages of development, homeostasis, and regeneration; differences in embryonic origin and adjacent tissue structures also affect SSPC regulation. As these SSPC niches are dynamic and highly specialized, changes under stress conditions and with aging can alter the cellular composition and molecular mechanisms in place, contributing to the dysregulation of local SSPCs and their activity in bone regeneration. Therefore, a better understanding of the different regulatory mechanisms for the distinct SSPCs in each skeletal compartment, and in different conditions, could provide answers to the existing knowledge gap and the impetus for realizing their potential in this biological and medical space. Here, we summarize the current scientific advances made in the study of the differential regulation pathways for distinct SSPCs in different bone compartments. We also discuss the physical, biological, and molecular factors that affect each skeletal compartment niche. Lastly, we look into how aging influences the regenerative capacity of SSPCs. Understanding these regulatory differences can open new avenues for the discovery of novel treatment approaches for calvarial or long bone repair.
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