Skeletal stem cells: origins, definitions, and functions in bone development and disease

Heng Feng , Bo Jiang , Wenhui Xing , Jun Sun , Matthew B. Greenblatt , Weiguo Zou

Life Medicine ›› 2022, Vol. 1 ›› Issue (3) : 276 -293.

PDF (1016KB)
Life Medicine ›› 2022, Vol. 1 ›› Issue (3) : 276 -293. DOI: 10.1093/lifemedi/lnac048
Review
Review

Skeletal stem cells: origins, definitions, and functions in bone development and disease

Author information +
History +
PDF (1016KB)

Abstract

Skeletal stem cells (SSCs) are tissue-specific stem cells that can self-renew and sit at the apex of their differentiation hierarchy, giving rise to mature skeletal cell types required for bone growth, maintenance, and repair. Dysfunction in SSCs is caused by stress conditions like ageing and inflammation and is emerging as a contributor to skeletal pathology, such as the pathogenesis of fracture nonunion. Recent lineage tracing experiments have shown that SSCs exist in the bone marrow, periosteum, and resting zone of the growth plate. Unraveling their regulatory networks is crucial for understanding skeletal diseases and developing therapeutic strategies. In this review, we systematically introduce the definition, location, stem cell niches, regulatory signaling pathways, and clinical applications of SSCs.

Keywords

bone development and repair / skeletal stem cells (SSCs) / the SSC niche / cell fate regulation / osteoblasts

Cite this article

Download citation ▾
Heng Feng, Bo Jiang, Wenhui Xing, Jun Sun, Matthew B. Greenblatt, Weiguo Zou. Skeletal stem cells: origins, definitions, and functions in bone development and disease. Life Medicine, 2022, 1(3): 276-293 DOI:10.1093/lifemedi/lnac048

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Serowoky MA, Arata CE, Crump JG, et al. Skeletal stem cells: insights into maintaining and regenerating the skeleton. Development 2020;147:dev179325.

[2]

Caplan AI. Mesenchymal stem cells. J Orthop Res 1991;9:641–50.

[3]

Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–7.

[4]

Robey P. “Mesenchymal stem cells”: fact or fiction, and implications in their therapeutic use. F1000Res 2017;6.

[5]

Chan CK, Seo EY, Chen JY, et al. Identification and specification of the mouse skeletal stem cell. Cell 2015;160:285–98.

[6]

Debnath S, Yallowitz AR, McCormick J, et al. Discovery of a periosteal stem cell mediating intramembranous bone formation. Nature 2018;562:133–9.

[7]

Logan M, Martin JF, Nagy A, et al. Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis 2002;33:77–80.

[8]

Greenbaum A, Hsu YM, Day RB, et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 2013;495:227–30.

[9]

Duchamp de Lageneste O, Julien A, Abou-Khalil R, et al. Periosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin. Nat Commun 2018;9:773.

[10]

Kawanami A, Matsushita T, Chan YY, et al. Mice expressing GFP and CreER in osteochondro progenitor cells in the periosteum. Biochem Biophys Res Commun 2009;386:477–82.

[11]

Park D, Spencer JA, Koh BI, et al. Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell 2012;10:259–72.

[12]

Mizoguchi T, Pinho S, Ahmed J, et al. Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development. Dev Cell 2014;29:340–9.

[13]

Muruganandan S, Pierce R, Teguh DA, et al. A FoxA2+ long-term stem cell population is necessary for growth plate cartilage regeneration after injury. Nat Commun 2022;13:2515.

[14]

Matthews BG, Novak S, Sbrana FV, et al., Heterogeneity of murine periosteum progenitors involved in fracture healing. Elife 2021;10:e58534.

[15]

Xu J, Wang Y, Li Z, et al.. PDGFRalpha reporter activity identifies periosteal progenitor cells critical for bone formation and fracture repair. Bone Res 2022;10:7.

[16]

Kuhn R, Torres RM. Cre/loxP recombination system and gene targeting. Methods Mol Biol 2002;180:175–204.

[17]

Mendez-Ferrer S, Michurina TV, Ferraro F, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010;466:829–34.

[18]

Ono N, Ono W, Mizoguchi T, et al. Vasculature-associated cells expressing nestin in developing bones encompass early cells in the osteoblast and endothelial lineage. Dev Cell 2014;29:330–9.

[19]

Zhou BO, Yue R, Murphy MM, et al. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 2014;15:154–68.

[20]

Shen B, Tasdogan A, Ubellacker JM, et al. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature 2021;591:438–44.

[21]

Seike M, Omatsu Y, Watanabe H, et al. Stem cell niche-specific Ebf3 maintains the bone marrow cavity. Genes Dev 2018;32:359–72.

[22]

Matsushita Y, Nagata M, Kozloff KM, et al. A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration. Nat Commun 2020;11:332.

[23]

Buhring HJ, Treml S, Cerabona F, et al. Phenotypic characterization of distinct human bone marrow-derived MSC subsets. Ann NY Acad Sci 2009;1176:124–34.

[24]

Sacchetti B, Funari A, Michienzi S, et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 2007;131:324–36.

[25]

Chan CKF, Gulati GS, Sinha R, et al. Identification of the Human Skeletal Stem Cell. Cell 2018;175:43–56.e21.

[26]

Mizuhashi K, Ono W, Matsushita Y, et al. Resting zone of the growth plate houses a unique class of skeletal stem cells. Nature 2018;563:254–8.

[27]

Sun J, Feng H, Xing W, al. Histone demethylase LSD1 is critical for endochondral ossification during bone fracture healing. Sci Adv 2020;6.

[28]

Shu HS, Liu YL, Tang XT, et al., Tracing the skeletal progenitor transition during postnatal bone formation. Cell Stem Cell 2021.

[29]

Ortinau LC, Wang H, Lei K, et al., Identification of functionally distinct Mx1+alphaSMA+ periosteal skeletal stem cells. Cell Stem Cell 2019;25:784–796.e785.

[30]

Worthley DL, Churchill M, Compton JT, et al. Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 2015;160:269–84.

[31]

Newton PT, Li L, Zhou B, et al. A radical switch in clonality reveals a stem cell niche in the epiphyseal growth plate. Nature 2019;567:234–8.

[32]

Nakashima K, Zhou X, Kunkel G, et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 2002;108:17–29.

[33]

Qiaoling ZLD, Yue R. Skeletal stem cells: a game changer of skeletal biology and regenerative medicine? Life Med 2022. doi: 10.1093/ lifemedi/lnac038/6698700.

[34]

Matsushita Y, Ono W, Ono N. Skeletal stem cells for bone development and repair: diversity matters. Curr Osteoporos Rep 2020;18:189–98.

[35]

Ara T, Tokoyoda K, Sugiyama T, et al. Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny. Immunity 2003;19:257–67.

[36]

Ding L, Saunders TL, Enikolopov G, et al. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 2012;481:457–62.

[37]

Tikhonova AN, Dolgalev I, Hu H, et al. The bone marrow microenvironment at single-cell resolution. Nature 2019;569:222–8.

[38]

Mo C, Guo J, Qin J, et al. Single-cell transcriptomics of LepR-positive skeletal cells reveals heterogeneous stress-dependent stem and progenitor pools. EMBO J 2022;41:e108415.

[39]

Baccin C, Al-Sabah J, Velten L, et al. Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat Cell Biol 2020;22:38–48.

[40]

Ding L, Morrison SJ. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 2013;495:231–5.

[41]

Kronenberg HM. Developmental regulation of the growth plate. Nature 2003;423:332–6.

[42]

Salhotra A, Shah HN, Levi B, et al. Mechanisms of bone development and repair. Nat Rev Mol Cell Biol 2020;21:696–711.

[43]

Zhou X, von der Mark K, Henry S, et al. Chondrocytes Transdifferentiate into Osteoblasts in Endochondral Bone during Development, Postnatal Growth and Fracture Healing in Mice. PLoS Genet 2014;10:e1004820.

[44]

Yang L, Tsang KY, Tang HC, et al. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc Natl Acad Sci USA 2014;111:12097–102.

[45]

Ono N, Ono W, Nagasawa T, et al. A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat Cell Biol 2014;16:1157–67.

[46]

Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol 2015;11:45–54.

[47]

Colnot C. Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration. J Bone Miner Res 2009;24:274–82.

[48]

Colnot C, Zhang X, Knothe Tate ML. Current insights on the regenerative potential of the periosteum: molecular, cellular, and endogenous engineering approaches. J Orthop Res 2012;30:1869–78.

[49]

Nakamura T, Imai Y, Matsumoto T, et al. Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell 2007;130:811–23.

[50]

Zhang Q, Zhou D, Wang H, et al. Heterotopic ossification of tendon and ligament. J Cell Mol Med 2020;24:5428–37.

[51]

Dey D, Bagarova J, Hatsell SJ, et al. Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification. Sci Transl Med 2016;8:366ra163.

[52]

Lees-Shepard JB, Nicholas SE, Stoessel SJ, et al. Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity. Elife 2018;7.

[53]

Lees-Shepard JB, Yamamoto M, Biswas AA, et al. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. Nat Commun 2018;9:471.

[54]

Julien A, Kanagalingam A, Martinez-Sarra E, et al. Direct contribution of skeletal muscle mesenchymal progenitors to bone repair. Nat Commun 2021;12:2860.

[55]

Agarwal S, Loder SJ, Cholok D, et al. Scleraxis-lineage cells contribute to ectopic bone formation in muscle and tendon. Stem Cells 2017;35:705–10.

[56]

Pryce BA, Brent AE, Murchison ND, et al. Generation of transgenic tendon reporters, ScxGFP and ScxAP, using regulatory elements of the scleraxis gene. Dev Dyn 2007;236:1677–82.

[57]

Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 1978;4:7–25.

[58]

Pinho S, Frenette PS. Haematopoietic stem cell activity and interactions with the niche. Nat Rev Mol Cell Biol 2019;20:303–20.

[59]

Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature 2014;505:327–34.

[60]

Kusumbe AP, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 2014;507:323–8.

[61]

Xu R, Yallowitz A, Qin A, et al. Targeting skeletal endothelium to ameliorate bone loss. Nat Med 2018;24:823–33.

[62]

Ambrosi TH, Marecic O, McArdle A, et al. Aged skeletal stem cells generate an inflammatory degenerative niche. Nature 2021;597:256–62.

[63]

Serre CM, Farlay D, Delmas PD, et al. Evidence for a dense and intimate innervation of the bone tissue, including glutamate-containing fibers. Bone 1999;25:623–9.

[64]

Chartier SR, Mitchell SA, Majuta LA, et al. The changing sensory and sympathetic innervation of the young, adult and aging mouse femur. Neuroscience 2018;387:178–90.

[65]

Wan QQ, Qin WP, Ma YX, et al. Crosstalk between bone and nerves within bone. Adv Sci (Weinh) 2021;8:2003390.

[66]

Ducy P, Amling M, Takeda S, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000;100:197–207.

[67]

Yue R, Zhou BO, Shimada IS, et al. Leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow. Cell Stem Cell 2016;18:782–96.

[68]

Zhou R, Yuan Z, Liu J, et al. Calcitonin gene-related peptide promotes the expression of osteoblastic genes and activates the WNT signal transduction pathway in bone marrow stromal stem cells. Mol Med Rep 2016;13:4689–96.

[69]

Heffner MA, Genetos DC, Christiansen BA. Bone adaptation to mechanical loading in a mouse model of reduced peripheral sensory nerve function. PLoS One 2017;12:e0187354.

[70]

Fu S, Mei G, Wang Z, et al. Neuropeptide substance P improves osteoblastic and angiogenic differentiation capacity of bone marrow stem cells in vitro. Biomed Res Int 2014;2014:1596023.

[71]

Niedermair T, Schirner S, Seebroker R, et al. Substance P modulates bone remodeling properties of murine osteoblasts and osteoclasts. Sci Rep 2018;8:9199.

[72]

Yahara M, Tei K, Tamura M. Inhibition of neuropeptide Y Y1 receptor induces osteoblast differentiation in MC3T3E1 cells. Mol Med Rep 2017;16:2779–84.

[73]

Sousa DM, Conceicao F, Silva DI, et al. Ablation of Y1 receptor impairs osteoclast bone-resorbing activity. Sci Rep 2016;6:33470.

[74]

Wee NKY, Sinder BP, Novak S, et al. Skeletal phenotype of the neuropeptide Y knockout mouse. Neuropeptides 2019;73:78–88.

[75]

Peng H, Hu B, Xie LQ, et al. A mechanosensitive lipolytic factor in the bone marrow promotes osteogenesis and lymphopoiesis. Cell Metab 2022.

[76]

Li CJ, Xiao Y, Sun Y-C, et al. Senescent immune cells release grancalcin to promote skeletal aging. Cell Metab 2022;34:184–5.

[77]

Kurenkova AD, Medvedeva EV, Newton PT, et al. Niches for skeletal stem cells of mesenchymal origin. Front Cell Dev Biol 2020;8:592.

[78]

Briscoe J, Therond PP. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 2013;14:416–29.

[79]

Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev 2008;22:2454–72.

[80]

Kronenberg HM. PTHrP and skeletal development. Ann N Y Acad Sci 2006;1068:1–13.

[81]

St-Jacques B, Hammerschmidt M, McMahon AP. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 1999;13:2072–86.

[82]

Kobayashi T, Chung U-il, Schipani E, et al. PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps. Development 2002;129:2977–86.

[83]

Kobayashi T, Soegiarto DW, Yang Y, et al. Indian hedgehog stimulates periarticular chondrocyte differentiation to regulate growth plate length independently of PTHrP. J Clin Invest 2005;115:1734–42.

[84]

Chen X, Macica CM, Dreyer BE, et al. Initial characterization of PTH-related protein gene-driven lacZ expression in the mouse. J Bone Miner Res 2006;21:113–23.

[85]

Mak KK, Kronenberg HM, Chuang P-T, et al. Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development 2008;135:1947–56.

[86]

Brechbiel JL, Ng JMY, Curran T. PTHrP treatment fails to rescue bone defects caused by hedgehog pathway inhibition in young mice. Toxicol Pathol 2011;39:478–85.

[87]

Maeda Y, Nakamura E, Nguyen MT, et al. Indian Hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone. Proc Natl Acad Sci USA 2007;104:6382–7.

[88]

Robinson GW, Kaste SC, Chemaitilly W, et al. Irreversible growth plate fusions in children with medulloblastoma treated with a targeted hedgehog pathway inhibitor. Oncotarget 2017;8:69295–302.

[89]

Kimura H, Ng JM, Curran T. Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. Cancer Cell 2008;13:249–60.

[90]

Tavella S, Biticchi R, Schito A, et al. Targeted expression of SHH affects chondrocyte differentiation, growth plate organization, and Sox9 expression. J Bone Miner Res 2004;19:1678–88.

[91]

Vortkamp A, Lee K, Lanske B, et al. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 1996;273:613–22.

[92]

Amano K, Densmore MJ, Lanske B. Conditional deletion of Indian hedgehog in limb mesenchyme results in complete loss of growth plate formation but allows mature osteoblast differentiation. J Bone Miner Res 2015;30:2262–72.

[93]

Long F, Chung U-il, Ohba S, et al. Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton. Development 2004;131:1309–18.

[94]

Roberts SJ, van Gastel N, Carmeliet G, et al. Uncovering the periosteum for skeletal regeneration: the stem cell that lies beneath. Bone 2015;70:10–8.

[95]

Boes M, Kain M, Kakar S, et al. Osteogenic effects of traumatic brain injury on experimental fracture-healing. J Bone Joint Surg Am 2006;88:738–43.

[96]

Xia W, Xie J, Cai Z, et al. Damaged brain accelerates bone healing by releasing small extracellular vesicles that target osteoprogenitors. Nat Commun 2021;12:6043.

[97]

Tomlinson RE, Li Z, Zhang Q, et al. NGF-TrkA signaling by sensory nerves coordinates the vascularization and ossification of developing endochondral bone. Cell Rep 2016;16:2723–35.

[98]

Asaumi K, Nakanishi T, Asahara H, et al. Expression of neurotrophins and their receptors (TRK) during fracture healing. Bone 2000;26:625–33.

[99]

Meyers CA, Lee S, Sono T, et al. A neurotrophic mechanism directs sensory nerve transit in cranial bone. Cell Rep 2020;31:107696.

[100]

Li Z, Meyers CA, Chang L, et al. Fracture repair requires TrkA signaling by skeletal sensory nerves. J Clin Invest 2019;129:5137–50.

[101]

Bishop JA, Palanca AA, Bellino MJ, et al. Assessment of compromised fracture healing. J Am Acad Orthop Surg 2012;20:273–82.

[102]

Watson EC, Adams RH. Biology of bone: the vasculature of the skeletal system. Cold Spring Harb Perspect Med 2018;8.

[103]

Hausman MR, Schaffler MB, Majeska RJ. Prevention of fracture healing in rats by an inhibitor of angiogenesis. Bone 2001;29:560–4.

[104]

Hallmann R, Feinberg RN, Latker CH, et al. Regression of blood vessels precedes cartilage differentiation during chick limb development. Differentiation 1987;34:98–105.

[105]

Maes C, Coenegrachts L, Stockmans I, et al. Placental growth factor mediates mesenchymal cell development, cartilage turnover, and bone remodeling during fracture repair. J Clin Invest 2006;116:1230–42.

[106]

Taylor DK, Meganck JA, Terkhorn S, et al. Thrombospondin-2 influences the proportion of cartilage and bone during fracture healing. J Bone Miner Res 2009;24:1043–54.

[107]

van Gastel N, Stegen S, Eelen G, et al. Lipid availability determines fate of skeletal progenitor cells via SOX9. Nature 2020;579:111–7.

[108]

Behr B, Leucht P, Longaker MT, et al. Fgf-9 is required for angiogenesis and osteogenesis in long bone repair. Proc Natl Acad Sci USA 2010;107:11853–8.

[109]

Coultas L, Chawengsaksophak K, Rossant J. Endothelial cells and VEGF in vascular development. Nature 2005;438:937–45.

[110]

Xie H, Cui Z, Wang L, et al. PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat Med 2014;20:1270–8.

[111]

Akeno N, Robins J, Zhang M, et al. Induction of vascular endothelial growth factor by IGF-I in osteoblast-like cells is mediated by the PI3K signaling pathway through the hypoxia-inducible factor-2alpha. Endocrinology 2002;143:420–5.

[112]

Hu K, Olsen BR. Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J Clin Invest 2016;126:509–26.

[113]

Xu J, Li Z, Tower RJ, et al. NGF-p75 signaling coordinates skeletal cell migration during bone repair. Sci Adv 2022;8:eabl5716.

[114]

Deng R, Li C, Wang X, et al. Periosteal CD68(+) F4/80(+) macrophages are mechanosensitive for cortical bone formation by secretion and activation of TGF-beta1. Adv Sci (Weinh) 2022;9:e2103343.

[115]

Nissen NN, Polverini PJ, Koch AE, et al. Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am J Pathol 1998;152:1445–52.

[116]

Schlundt C, El Khassawna T, Serra A, et al. Macrophages in bone fracture healing: their essential role in endochondral ossification. Bone 2018;106:78–89.

[117]

Vi L, Baht GS, Soderblom EJ, et al. Macrophage cells secrete factors including LRP1 that orchestrate the rejuvenation of bone repair in mice. Nat Commun 2018;9:5191.

[118]

Gao B, Deng R, Chai Y, et al. Macrophage-lineage TRAP+ cells recruit periosteum-derived cells for periosteal osteogenesis and regeneration. J Clin Invest 2019;129:2578–94.

[119]

Tsuji K, Bandyopadhyay A, Harfe BD, et al. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet 2006;38:1424–9.

[120]

McBride-Gagyi SH, McKenzie JA, Buettmann EG, et al. Bmp2 conditional knockout in osteoblasts and endothelial cells does not impair bone formation after injury or mechanical loading in adult mice. Bone 2015;81:533–43.

[121]

Le AX, Miclau T, Hu D, et al. Molecular aspects of healing in stabilized and non-stabilized fractures. J Orthop Res 2001;19:78–84.

[122]

Wang Q, Huang C, Zeng F, et al. Activation of the Hh pathway in periosteum-derived mesenchymal stem cells induces bone formation in vivo: implication for postnatal bone repair. Am J Pathol 2010;177:3100–11.

[123]

Kuwahara ST, Serowoky MA, Vakhshori V, et al. Sox9+ messenger cells orchestrate large-scale skeletal regeneration in the mammalian rib. Elife 2019;8.

[124]

Niederreither K, Dolle P. Retinoic acid in development: towards an integrated view. Nat Rev Genet 2008;9:541–53.

[125]

Michaelsson K, Lithell H, Vessby B, et al. Serum retinol levels and the risk of fracture. N Engl J Med 2003;348:287–94.

[126]

Mak KK, Bi Y, Wan C, et al. Hedgehog signaling in mature osteoblasts regulates bone formation and resorption by controlling PTHrP and RANKL expression. Dev Cell 2008;14:674–88.

[127]

Yang W, Wang J, Moore DC, et al. Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling. Nature 2013;499:491–5.

[128]

Bowen ME, Ayturk UM, Kurek KC, et al. SHP2 regulates chondrocyte terminal differentiation, growth plate architecture and skeletal cell fates. PLoS Genet 2014;10:e1004364.

[129]

Marecic O, Tevlin R, McArdle A, et al. Identification and characterization of an injury-induced skeletal progenitor. Proc Natl Acad Sci USA 2015;112:9920–5.

[130]

Tevlin R, Seo EY, Marecic O, et al Pharmacological rescue of diabetic skeletal stem cell niches. Sci Transl Med 2017;9.

[131]

Sun J, Shin DY, Eiseman M, et al. SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts. Nat Commun 2021;12:4611.

[132]

Nusse R, Clevers H. Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell 2017;169:985–99.

[133]

Hallett SA, Matsushita Y, Ono W, et al. Chondrocytes in the resting zone of the growth plate are maintained in a Wnt-inhibitory environment. Elife 2021;10.

[134]

Liu A, Niswander LA. Bone morphogenetic protein signalling and vertebrate nervous system development. Nat Rev Neurosci 2005;6:945–54.

[135]

Bandyopadhyay A, Tsuji K, Cox K, et al. Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet 2006;2:e216.

[136]

Salazar VS, Capelo LP, Cantu C, et al. Reactivation of a developmental Bmp2 signaling center is required for therapeutic control of the murine periosteal niche. Elife 2019;8.

[137]

Ransom RC, Carter AC, Salhotra A, et al. Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration. Nature 2018;563:514–21.

[138]

Papageorgiou P, Vallmajo-Martin Q, Kisielow M, et al. Expanded skeletal stem and progenitor cells promote and participate in induced bone regeneration at subcritical BMP-2 dose. Biomaterials 2019;217:119278.

[139]

Bez M, Sheyn D, Tawackoli W, et al. In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs. Sci Transl Med 2017;9.

[140]

Sanghani-Kerai A, Osagie-Clouard L, Blunn G, et al. The influence of age and osteoporosis on bone marrow stem cells from rats. Bone Joint Res 2018;7:289–97.

[141]

Lam Y. Bone tumors: benign bone tumors. FP Essent 2020;493:11–21.

[142]

Han Y, Feng H, Sun J, et al. Lkb1 deletion in periosteal mesenchymal progenitors induces osteogenic tumors through mTORC1 activation. J Clin Invest 2019;130.

[143]

Kan C, Ding N, Yang J, et al. BMP-dependent, injury-induced stem cell niche as a mechanism of heterotopic ossification. Stem Cell Res Ther 2019;10:14.

[144]

Feng H, Xing W, Han Y, et al. Tendon-derived cathepsin K-expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification. J Clin Invest 2020;130:6354–65.

[145]

Deng Q, Li P, Che M, et al. Activation of hedgehog signaling in mesenchymal stem cells induces cartilage and bone tumor formation via Wnt/beta-Catenin. Elife 2019;8.

[146]

Chen Y, Shen W, Tang C, et al. Targeted pathological collagen delivery of sustained-release rapamycin to prevent heterotopic ossification. Sci Adv 2020;6:eaay9526.

[147]

Qureshi AT, Dey D, Sanders EM, et al. Inhibition of mammalian target of rapamycin signaling with rapamycin prevents trauma-induced heterotopic ossification. Am J Pathol 2017;187:2536–45.

[148]

Jin YZ, Lee JH. Mesenchymal stem cell therapy for bone regeneration. Clin Orthop Surg 2018;10:271–8.

[149]

Murphy MP, Koepke LS, Lopez MT, et al. Articular cartilage regeneration by activated skeletal stem cells. Nat Med 2020;26:1583–92.

[150]

Chen C, Liao Y, Peng G. Connecting past and present: single-cell lineage tracing. Protein Cell 2022;13:790–807.

[151]

Patel SH, Christodoulou C, Weinreb C, et al. Lifelong multilineage contribution by embryonic-born blood progenitors. Nature 2022;606:747–53.

[152]

Pei W, Shang F, Wang X, et al. Resolving fates and single-cell transcriptomes of hematopoietic stem cell clones by polyloxexpress barcoding. Cell Stem Cell 2020;27:383p. 383–395.e8.

RIGHTS & PERMISSIONS

The Author(s) 2022. Published by Oxford University Press on behalf of Higher Education Press.

AI Summary AI Mindmap
PDF (1016KB)

927

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/