{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T06:50:28Z","timestamp":1759042228842,"version":"3.41.2"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T00:00:00Z","timestamp":1675036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>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 <jats:italic>in vitro<\/jats:italic> 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.<\/jats:p>","DOI":"10.3389\/fphys.2023.1106474","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T04:44:46Z","timestamp":1675053886000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Prx1 cell subpopulations identified in various tissues with diverse quiescence and activation ability following fracture and BMP2 stimulation"],"prefix":"10.3389","volume":"14","author":[{"given":"Yu","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian","family":"Ilinski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louis C.","family":"Gerstenfeld","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beth","family":"Bragdon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"189","DOI":"10.3389\/fcell.2019.00189","article-title":"A revised perspective of skeletal stem cell biology","volume":"7","author":"Batista","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1097\/SCS.0b013e318052fe3d","article-title":"Osteogenic capacities of tibial and cranial periosteum: A biochemical and histologic study","volume":"19","author":"Bilkay","year":"2008","journal-title":"J. Craniofac Surg."},{"key":"B3","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1002\/jor.1100020115","article-title":"Production of a standard closed fracture in laboratory animal bone","volume":"2","author":"Bonnarens","year":"1984","journal-title":"J. Orthop. Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1002\/jcp.24705","article-title":"Intrinsic sex-linked variations in osteogenic and adipogenic differentiation potential of bone marrow multipotent stromal cells","volume":"230","author":"Bragdon","year":"2015","journal-title":"J. Cell. Physiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2550","DOI":"10.1002\/jcp.30728","article-title":"Post natal expression of Prx1 labels appendicular restricted progenitor cell populations of multiple tissues","volume":"237","author":"Bragdon","year":"2022","journal-title":"J. Cell Physiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.bone.2017.04.002","article-title":"Earliest phases of chondrogenesis are dependent upon angiogenesis during ectopic bone formation in mice","volume":"101","author":"Bragdon","year":"2017","journal-title":"Bone"},{"key":"B7","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41580-022-00510-w","article-title":"Ageing and rejuvenation of tissue stem cells and their niches","volume":"24","author":"Brunet","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/s1471-4914(01)02016-0","article-title":"Mesenchymal stem cells: Building blocks for molecular medicine in the 21st century","volume":"7","author":"Caplan","year":"2001","journal-title":"Trends Mol. Med."},{"article-title":"The immune properties of mesenchymal stem cells","year":"2007","author":"Castillo","key":"B44"},{"key":"B9","doi-asserted-by":"publisher","first-page":"3673","DOI":"10.1038\/ncomms4673","article-title":"G-protein stimulatory subunit alpha and Gq\/11\u03b1 G-proteins are both required to maintain quiescent stem-like chondrocytes","volume":"5","author":"Chagin","year":"2014","journal-title":"Nat. Commun."},{"key":"B45","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1038\/nature07547","article-title":"Endochondral ossification is required for haematopoietic stem-cell niche formation","volume":"457","author":"Chan","year":"2009","journal-title":"Endochondral ossification is required for haematopoietic stem-cell niche formation"},{"key":"B10","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/j.cell.2014.12.002","article-title":"Identification and specification of the mouse skeletal stem cell","volume":"160","author":"Chan","year":"2015","journal-title":"Cell"},{"key":"B11","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1016\/j.neuron.2014.02.039","article-title":"Prospective identification and purification of quiescent adult neural stem cells from their in vivo niche","volume":"82","author":"Codega","year":"2014","journal-title":"Neuron"},{"key":"B12","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1359\/jbmr.081003","article-title":"Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration","volume":"24","author":"Colnot","year":"2009","journal-title":"J. Bone Mineral Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1002\/jor.22181","article-title":"Current insights on the regenerative potential of the periosteum: Molecular, cellular, and endogenous engineering approaches","volume":"30","author":"Colnot","year":"2012","journal-title":"J. Orthop. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1007\/978-1-62703-989-5_3","article-title":"Generation of closed transverse fractures in small animals","volume":"1130","author":"de Giacomo","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/s41586-018-0554-8","article-title":"Discovery of a periosteal stem cell mediating intramembranous bone formation","volume":"562","author":"Debnath","year":"2018","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1038\/s41467-018-03124-z","article-title":"Periosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin","volume":"9","author":"Duchamp de Lageneste","year":"2018","journal-title":"Nat. Commun."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1525","DOI":"10.1002\/jbmr.4020","article-title":"Murine tissue-resident PDGFR\u03b1+ fibro-adipogenic progenitors spontaneously acquire osteogenic phenotype in an altered inflammatory environment","volume":"35","author":"Eisner","year":"2020","journal-title":"J. Bone Mineral Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2845","DOI":"10.3390\/ijerph15122845","article-title":"Incidence, costs and predictors of non-union, delayed union and mal-union following long bone fracture","volume":"15","author":"Ekegren","year":"2018","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1002\/stem.476","article-title":"Adult stem cells exhibit global suppression of RNA polymerase II serine-2 phosphorylation","volume":"28","author":"Freter","year":"2010","journal-title":"Stem Cells"},{"key":"B47","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.4049\/jimmunol.133.4.1710","article-title":"Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67","volume":"133","author":"Gerdes","year":"1984","journal-title":"J. Immun."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1038\/nprot.2008.142","article-title":"Isolation of a slowly adhering cell fraction containing stem cells from murine skeletal muscle by the preplate technique","volume":"3","author":"Gharaibeh","year":"2008","journal-title":"Nat. Protoc."},{"key":"B20","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1038\/nature11926","article-title":"CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance","volume":"495","author":"Greenbaum","year":"2013","journal-title":"Nature"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1038\/nprot.2018.041","article-title":"Isolation and functional assessment of mouse skeletal stem cell lineage","volume":"13","author":"Gulati","year":"2018","journal-title":"Nat. Protoc."},{"key":"B49","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1126\/science.1181348","article-title":"Systematic analysis of human protein complexes identifies chromosome segregation proteins","volume":"328","author":"Hutchins","year":"2010","journal-title":"Science"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12712","article-title":"Immune modulation by mesenchymal stem cells","volume":"53","author":"Jiang","year":"2020","journal-title":"Cell Prolif."},{"key":"B21","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/ncb2015","article-title":"Muscle injury activates resident fibro\/adipogenic progenitors that facilitate myogenesis","volume":"12","author":"Joe","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2860","DOI":"10.1038\/s41467-021-22842-5","article-title":"Direct contribution of skeletal muscle mesenchymal progenitors to bone repair","volume":"12","author":"Julien","year":"2021","journal-title":"Nat. Commun."},{"key":"B23","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.bbrc.2009.06.059","article-title":"Mice expressing GFP and CreER in osteochondro progenitor cells in the periosteum","volume":"386","author":"Kawanami","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B24","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1210\/jc.2013-2352","article-title":"Five-year relative survival of patients with osteoporotic hip fracture","volume":"99","author":"Lee","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B25","doi-asserted-by":"publisher","first-page":"110785","DOI":"10.1016\/j.celrep.2022.110785","article-title":"Identification of distinct non-myogenic skeletal-muscle-resident mesenchymal cell populations","volume":"39","author":"Leinroth","year":"2022","journal-title":"Cell Rep."},{"key":"B26","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.bone.2015.06.013","article-title":"Skeletal muscle-resident MSCs and bone formation","volume":"80","author":"Lemos","year":"2015","journal-title":"Bone"},{"key":"B51","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1002\/gene.10092","article-title":"Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer","volume":"33","author":"Logan","year":"2002","journal-title":"Genesis"},{"key":"B27","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/9780470942390.mo140161","article-title":"Mouse models in orthopaedic research: An overview of fracture, marrow ablation, and distraction osteogenesis","volume":"5","author":"Lybrand","year":"2015","journal-title":"Curr. Protoc. Mouse Biol.10.1002\/9780470942390.mo140161"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1016\/J.JBIOMECH.2008.01.029","article-title":"An improved murine femur fracture device for bone healing studies","volume":"41","author":"Marturano","year":"2008","journal-title":"J. Biomech."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.3390\/cells10051145","article-title":"Regulation of adult mammalian neural stem cells and neurogenesis by cell extrinsic and intrinsic factors","volume":"10","author":"Matsubara","year":"2021","journal-title":"Cells"},{"key":"B30","doi-asserted-by":"publisher","first-page":"e58534","DOI":"10.7554\/eLife.58534","article-title":"Heterogeneity of murine periosteum progenitors involved in fracture healing","volume":"10","author":"Matthews","year":"2021","journal-title":"Elife"},{"key":"B31","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1038\/nature09262","article-title":"Mesenchymal and haematopoietic stem cells form a unique bone marrow niche","volume":"466","author":"M\u00e9ndez-Ferrer","year":"2010","journal-title":"Nature"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e10172","DOI":"10.1002\/jbm4.10172","article-title":"Heterotopic ossification: A comprehensive review","volume":"3","author":"Meyers","year":"2019","journal-title":"JBMR Plus"},{"key":"B33","doi-asserted-by":"publisher","first-page":"56641","DOI":"10.1371\/journal.pone.0056641","article-title":"Osteogenic differentiation capacity of human skeletal muscle-derived progenitor cells","volume":"8","author":"Oishi","year":"2013","journal-title":"PLoS One"},{"key":"B34","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1016\/j.stem.2019.11.003","article-title":"Identification of functionally distinct Mx1+\u03b1SMA+ periosteal skeletal stem cells","volume":"25","author":"Ortinau","year":"2019","journal-title":"Cell Stem Cell"},{"key":"B35","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.stem.2012.02.003","article-title":"Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration","volume":"10","author":"Park","year":"2012","journal-title":"Cell Stem Cell"},{"key":"B52","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/nature13255","article-title":"mTORC1 controls the adaptive transition of quiescent stem cells from G 0 to G Alert","volume":"510","author":"Rodgers","year":"2014","journal-title":"Nature"},{"key":"B36","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/J.DIFF.2008.09.007","article-title":"The contribution of different cell lineages to bone repair: Exploring a role for muscle stem cells","volume":"77","author":"Schindeler","year":"2009","journal-title":"Differentiation"},{"key":"B53","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/(SICI)1097-4652(200003)182:3<311::AID-JCP1>3.0.CO;2-9","article-title":"The Ki-67 protein: From the known and the unknown","volume":"182","author":"Scholzen","year":"2000","journal-title":"J. Cell Physiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/s41580-021-00421-2","article-title":"Control of satellite cell function in muscle regeneration and its disruption in ageing","volume":"23","author":"Sousa-Victor","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1038\/nature20123","article-title":"Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma","volume":"539","author":"Tirosh","year":"2016","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1038\/ng1916","article-title":"BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing","volume":"38","author":"Tsuji","year":"2006","journal-title":"Nat. Genet."},{"key":"B39","doi-asserted-by":"publisher","first-page":"dev165084","DOI":"10.1242\/dev.165084","article-title":"Stem cell quiescence: The challenging path to activation","volume":"148","author":"Urb\u00e1n","year":"2021","journal-title":"Development"},{"key":"B40","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1359\/jbmr.091021","article-title":"Acute phosphate restriction leads to impaired fracture healing and resistance to BMP-2","volume":"25","author":"Wigner","year":"2010","journal-title":"J. bone mineral Res. official J. Am. Soc. Bone Mineral Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1002\/jbmr.1562","article-title":"Multipotent progenitors resident in the skeletal muscle interstitium exhibit robust BMP-dependent osteogenic activity and mediate heterotopic ossification","volume":"27","author":"Wosczyna","year":"2012","journal-title":"J. Bone Mineral Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1016\/j.celrep.2015.08.083","article-title":"Calcitonin receptor signaling inhibits muscle stem cells from escaping the quiescent state and the niche","volume":"13","author":"Yamaguchi","year":"2015","journal-title":"Cell Rep."},{"key":"B43","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.stem.2014.06.008","article-title":"Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow","volume":"15","author":"Zhou","year":"2014","journal-title":"Cell Stem Cell"}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2023.1106474\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T04:44:52Z","timestamp":1675053892000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2023.1106474\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,30]]},"references-count":54,"alternative-id":["10.3389\/fphys.2023.1106474"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2023.1106474","relation":{},"ISSN":["1664-042X"],"issn-type":[{"type":"electronic","value":"1664-042X"}],"subject":[],"published":{"date-parts":[[2023,1,30]]},"article-number":"1106474"}}