Wnt4 from the Niche Controls the Mechano-Properties and Quiescent State of Muscle Stem Cells
Open accessAbstract
Satellite cells (SCs) reside in a dormant state during tissue homeostasis. The specific paracrine agents and niche cells that maintain SC quiescence remain unknown. We find that Wnt4 produced by the muscle fiber maintains SC quiescence through RhoA. Using cell-specific inducible genetics, we find that a Wnt4-Rho signaling axis constrains SC numbers and activation during tissue homeostasis in adult mice. Wnt4 activates Rho in quiescent SCs to maintain mechanical strain, restrict movement in the niche, and repress YAP. The induction of YAP upon disruption of RhoA is essential for SC activation under homeostasis. In the context of injury, the loss of Wnt4 from the niche accelerates SC activation and muscle repair, whereas overexpression of Wnt4 transitions SCs into a deeper state of quiescence and delays muscle repair. In conclusion, the SC pool undergoes dynamic transitions during early activation with changes in mechano-properties and cytoskeleton signaling preceding cell-cycle entry.
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Wnt4 is secreted by myofibers to maintain SC quiescence.
“This is critical because Wnt4 is secreted by myofibers to maintain SC quiescence.”
From In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (2021) · cites this paper as [23]
Wnt4 is a recently identified paracrine factor that is secreted from myofibers.
“Wnt family member 4 (Wnt4) is a recently identified paracrine factor that is secreted from myofibers23.”
From In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (2021) · cites this paper as [23]
Loss of Wnt4 in myofibers induces the activation of SCs and accelerates muscle regeneration.
“Loss of Wnt4 in myofibers induces the activation of SCs and accelerates muscle regeneration23.”
From In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (2021) · cites this paper as [23]
Diminishment of the SC pool is not observed when SCs-SC niche molecular interactions are interrupted in muscles lacking Wnt4, N-, and M-cadherins or syndecan-3.
“Interestingly, diminishment of the SC pool is not observed when SCs-SC niche molecular interactions are interrupted in muscles lacking Wnt4, N-, and M-cadherins or syndecan-323,39,40.”
From In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (2021) · cites this paper as [23]
The effect of cyclic Wnt4 knockdown on muscle regeneration is similar to permanent Wnt4 knockdown.
“Interestingly, the effect of cyclic Wnt4 knockdown on muscle regeneration is similar to permanent Wnt4 knockdown23.”
From In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (2021) · cites this paper as [23]
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van Velthoven, C. T. J., de Morree, A., Egner, I. M., Brett, J. O., & Rando, T. A. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.037 · Cited by 235 · see citing works
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BackgroundSelf-citationNiche Cadherins Control the Quiescence-to-Activation Transition in Muscle Stem Cells
Goel, A. J., Rieder, M.-K., Arnold, H.-H., Radice, G. L., & Krauss, R. S. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.102 · Cited by 146 · cited 4× · see citing works
“Consistent with the notion that quiescence is essential for adult stem cell preservation, deregulation of quiescence in muscle stem cells during tissue homeostasis, leads to their depletion through apoptosis, precocious differentiation or incorporation into the center of the muscle fiber-reminiscent of a regenerative…”
BackgroundResultInfluentialJackson, B., Peyrollier, K., Pedersen, E., Basse, A. L., Karlsson, R. T. G., Wang, Z., Lefever, T., Ochsenbein, A. M., Schmidt, G., Aktories, K., et al. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e09-10-0859 · Cited by 144 · cited 3× · see citing works
“Previously published HSACreMER (McCarthy et al., 2012), Wnt4flox/flox (Kobayashi et al., 2011), Wnt4OX/+ (Lee and Behringer, 2007), Porcnflox/flox (Roman et al., 2014), Pax7CreER (Nishijo et al., 2009), RhoAflox/+ (Jackson et al., 2011), YAPflox/flox (Xin et al., 2011) were used in this study.”
MethodBiomarker system for studying muscle, stem cells, and cancer in vivo
Nishijo, K., Hosoyama, T., Bjornson, C. R. R., Schaffer, B. S., Prajapati, S. I., Bahadur, A. N., Hansen, M. S. T., Blandford, M. C., McCleish, A. T., Rubin, B. P., et al. (2009) · The FASEB Journal · doi:10.1096/fj.08-128116 · Cited by 132 · see citing works
Notch-Induced miR-708 Antagonizes Satellite Cell Migration and Maintains Quiescence
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“In line with the concept that the cytoskeletal machinery functions as an early regulator of SC activation, mir-708, upregulates Tensin3, a positive regulator of pFAK activity, to delay cell cycle entry (Baghdadi et al., 2018).”
BackgroundSun, C., Mello, V. D., Mohamed, A. D., Quiroga, H. P. O., García-Muñoz, A., Bloshi, A. A., Tremblay, A., von Kriegsheim, A., Collie-Duguid, E. S. R., Vargesson, N., et al. (2017) · Stem Cells · doi:10.1002/stem.2652 · Cited by 128 · cited 1× · see citing works
“, 2011) and is required for SC activation (Judson et al., 2012; Sun et al., 2017).”
BackgroundPrecise Regulation of Porcupine Activity Is Required for Physiological Wnt Signaling
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“Loss of NMJ activity results in muscle fiber atrophy and a welldefined ‘denervation’ transcriptional response (Hyatt et al., 2003; Windisch et al., 1998).”
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β-Catenin Activation in Muscle Progenitor Cells Regulates Tissue Repair
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“Wnt signaling plays a critical role in coordinating SC state transitions from asymmetric fate, proliferation, commitment and differentiation (Brack et al., 2008; Brack et al., 2009; Jones et al., 2015; Lacour et al., 2017b; Le Grand et al., 2009; Parisi et al., 2015b; Rudolf et al., 2016).”
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“…Wnt11 and Wnt4 signal via Frizzled receptors to Dishevelled (Dvl), an adaptor protein which becomes polarized at the apical membrane to regulate morphology, polarization and migration of cell structures in the developing epithelium (Jussila and Ciruna, 2017; Sokol, 2015; Yang and Mlodzik, 2015).”
Backgroundβ-Catenin is essential for Müllerian duct regression during male sexual differentiation
Kobayashi, A., Stewart, C. A., Wang, Y., Fujioka, K., Thomas, N. C., Jamin, S. P., & Behringer, R. R. (2011) · Development · doi:10.1242/dev.056143 · Cited by 97 · see citing works
Skeletal Muscle as a Paradigm for Regenerative Biology and Medicine
Gayraud-Morel, B., Chrétien, F. C., & Tajbakhsh, S. (2009) · Regenerative Medicine · doi:10.2217/17460751.4.2.293 · Cited by 93 · see citing works
Wnt/β-catenin controls follistatin signalling to regulate satellite cell myogenic potential
Jones, A., Price, F. D., Grand, F. L., Soleimani, V. D., Dick, S. A., Megeney, L. A., & Rudnicki, M. A. (2015) · Skeletal Muscle · doi:10.1186/s13395-015-0038-6 · Cited by 90 · see citing works
Murphy, M. M., Keefe, A., Lawson, J. A., Flygare, S. D., Yandell, M. D., & Kardon, G. (2014) · Stem Cell Reports · doi:10.1016/j.stemcr.2014.06.019 · Cited by 90 · see citing works
Wnt4 Participates in the Formation of Vertebrate Neuromuscular Junction
Strochlic, L., Falk, J., Goillot, E., Sigoillot, S. M., Bourgeois, F., Delers, P., Rouvière, J. O., Swain, A., Castellani, V., Schaeffer, L., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029976 · Cited by 89 · cited 1× · see citing works
“Wnt4 is known to play a role in vertebrate neuromuscular junction (NMJ) formation (Strochlic et al., 2012).”
BackgroundNiche WNT5A regulates the actin cytoskeleton during regeneration of hematopoietic stem cells
Schreck, C., Istvánffy, R., Ziegenhain, C., Landspersky, T., Ruf, F., Henkel, L., Gärtner, F., Vieth, B., Florian, M. C., Mende, N., et al. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20151414 · Cited by 57 · cited 1× · see citing works
“The Rho family of GTPases play a key role in cytoskeletal remodeling (Sit and Manser, 2011) and has been implicated in HSC self-renewal (Schreck et al., 2017).”
BackgroundKimmel, J. C., Chang, A. Y., Brack, A. S., & Marshall, W. F. (2018) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005927 · Cited by 54 · cited 1× · see citing works
“Using time-lapse imaging we recently demonstrated that SC motility occurs early in the activation response (Kimmel et al., 2018).”
Coordinated action of Axin1 and Axin2 suppresses β-catenin to regulate muscle stem cell function
Figeac, N., & Zammit, P. S. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.03.025 · Cited by 53 · see citing works
Lacour, F., Vezin, E., Bentzinger, C. F., Sincennes, M., Giordani, L., Ferry, A., Mitchell, R., Patel, K., Rudnicki, M. A., Chaboissier, M., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.036 · Cited by 52 · see citing works
APC is required for muscle stem cell proliferation and skeletal muscle tissue repair
Parisi, A., Lacour, F., Giordani, L., Colnot, S., Maire, P., & Grand, F. L. (2015) · The Journal of Cell Biology · doi:10.1083/jcb.201501053 · Cited by 46 · see citing works
Conditional Expression of Wnt4 during Chondrogenesis Leads to Dwarfism in Mice
Lee, H., & Behringer, R. R. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000450 · Cited by 45 · cited 2× · see citing works
“To determine if increasing Wnt4 in the niche reinforces quiescence, we used an inducible transgenic gain-of-function approach to overexpress Wnt4 (Lee and Behringer, 2007) in adult muscle fibers (Tg: HSACreMER/+; Wnt4OX/+ herein called as Myofiber (MF)Wnt4OX/+) (Fig.”
MethodA CREB-MPP7-AMOT Regulatory Axis Controls Muscle Stem Cell Expansion and Self-Renewal Competence
Li, L., & Fan, C. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.031 · Cited by 37 · cited 1× · see citing works
“For example, Mpp7, a component of Hippo signaling, is expressed in QSCs to inhibit YAP activity and thus limit SC activation (Li and Fan, 2017).”
BackgroundJussila, M., & Ciruna, B. G. (2017) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.267 · Cited by 18 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- Lacour F, Vezin E, Bentzinger CF, Sincennes MC, Giordani L, Ferry A, Mitchell R, Patel K, Rudnicki MA, Chaboissier MC, (2017b). R-spondin1 Controls Muscle Cell Fusion through Dual Regulation of Antagonistic Wnt Signaling Pathways. Cell reports 18, 2320– 2330. 28273449 PMC5357729
- Mourikis P, Sambasivan R, Castel D, Rocheteau P, Bizzarro V, and Tajbakhsh S (2012). A critical requirement for notch signaling in maintenance of the quiescent skeletal muscle stem cell state. Stem Cells 30, 243– 252. 22069237
- Parisi A, Lacour F, Giordani L, Colnot S, Maire P, and Le Grand F (2015b). APC is required for muscle stem cell proliferation and skeletal muscle tissue repair. The Journal of cell biology 210, 717– 726. 26304725 PMC4555822
Cited by
Sorted by citations
Control of satellite cell function in muscle regeneration and its disruption in ageing
Sousa-Victor, P., García-Prat, L., & Muñoz-Cánoves, P. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00421-2 · Cited by 476 · see citing works
Perspectives on skeletal muscle stem cells
Relaix, F., Bencze, M., Borok, M. J., Vartanian, A. D., Gattazzo, F., Mademtzoglou, D., Perez-Diaz, S., Prola, A., Fernandez, P. C. R., Rotini, A., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20760-6 · Cited by 389 · see citing works
Tissue Stem Cells: Architects of Their Niches
Fuchs, E., & Blau, H. M. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.09.011 · Cited by 332 · see citing works
“Even for universal regulators such as WNTs, low levels of WNT signaling may favor stem cell quiescence, moderate levels may favor stem cell proliferation, and high WNT signaling can favor differentiation (Brack et al., 2008; Eliazer et al., 2019; Ito et al., 2007; Lien et al., 2014; Rudolf et al., 2016; Seale et al.,…”
BackgroundInfluentialCellular Mechanisms and Regulation of Quiescence
Marescal, O., & Cheeseman, I. M. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.09.029 · Cited by 284 · see citing works
“In addition to withholding growth factors, the niche prevents inappropriate proliferation by producing quiescence-inducing soluble factors, including TGF-β1 (Batard et al., 2000; Ducos et al., 2000), Wnt4 (Eliazer et al., 2019), IL-6 cytokines (Sampath et al., 2018), and other factors (Delgado et al., 2014; Kalamakis…”
Tissue mechanics in stem cell fate, development, and cancer
Hayward, M.-K., Muncie, J. M., & Weaver, V. M. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.05.011 · Cited by 154 · see citing works
Self-citationMuncie, J. M., Ayad, N. M. E., Lakins, J. N., Xue, X., Fu, J., & Weaver, V. M. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.10.015 · Cited by 158 · see citing works
“Notably, Wnt/b-catenin signaling is conserved among model organisms and plays multiple roles throughout the courseofembryogenesisand inadult stemcells (Clevers, 2006;Eliazer et al., 2019; Petersen and Reddien, 2009; van Amerongen and Nusse, 2009), implying that the tension-regulated activation of the pathway that we i…”
BackgroundSelf-citationStem cell quiescence: the challenging path to activation
Urbán, N., & Cheung, T. H. (2021) · Development · doi:10.1242/dev.165084 · Cited by 154 · see citing works
“For example, muscle fibres secreteWnt4, which maintains the quiescent state of MuSCs by restricting their mobility and by controlling YAP activation through a RhoA-dependent mechanism (Eliazer et al., 2019).”
BackgroundMechanical state transitions in the regulation of tissue form and function
Mao, Y., & Wickström, S. A. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00719-x · Cited by 138 · see citing works
Ma, N., Chen, D., Lee, J.-H., Kuri, P., Hernandez, E. B., Kocan, J., Mahmood, H., Tichy, E. D., Rompolas, P., & Mourkioti, F. (2022) · Science Advances · doi:10.1126/sciadv.abn0485 · Cited by 118 · see citing works
“The impact of microenvironmental stiffness on MuSC activation ( 5 ) as well as the importance of mechanoregulation of stem cells across different contexts from development to differentiation are becoming increasingly appreciated ( 3 , 4 , 24 ).”
InfluentialFusion and beyond: Satellite cell contributions to loading-induced skeletal muscle adaptation
Murach, K. A., Fry, C. S., Dupont‐Versteegden, E. E., McCarthy, J. J., & Peterson, C. A. (2021) · The FASEB Journal · doi:10.1096/fj.202101096r · Cited by 120 · see citing works
Wang, C., Rabadan Ros, R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., Guillen-Guillen, I., Huang, L., Hishida, T., Liao, H.-K., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23353-z · Cited by 119 · see citing works
Satellite cells in ageing: use it or lose it
Chen, W., Datzkiw, D., & Rudnicki, M. A. (2020) · Open Biology · doi:10.1098/rsob.200048 · Cited by 116 · see citing works
Silver, J. S., Günay, K. A., Cutler, A. A., Vogler, T. O., Brown, T. E., Pawlikowski, B. T., Bednarski, O. J., Bannister, K. L., Rogowski, C. J., Mckay, A. G., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe4501 · Cited by 117 · see citing works
“Although muscle stiffness is low (E′ = 5 kPa) due to the degradation of injured tissue, YAP and TAZ levels are elevated in MuSCs (35), as YAP is required to initiate MuSC activation and proliferation (10).”
BackgroundInfluentialThe emergence of the stem cell niche
Hicks, M. R., & Pyle, A. D. (2022) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.07.003 · Cited by 112 · see citing works
“Regulation of the niche has also been accomplished using receptor–ligand combinations, such as using myofiber-derived Wnt4, which was shown to regulate the stem cell niche set point [98], and knockout of signaling pathways such as with Stat3 in the SCs that makes them nonresponsive to myofiber-induced signals such as…”
Advances and Challenges in Cell Biology for Cultured Meat
Martins, B., Bister, A., Dohmen, R. G. J., Gouveia, M. A., Hueber, R., Melzener, L., Meßmer, T., Papadopoulos, J., Pimenta, J., Raina, D., et al. (2023) · Annual Review of Animal Biosciences · doi:10.1146/annurev-animal-021022-055132 · Cited by 113 · see citing works
Novoseletskaya, E., Grigorieva, O., Nimiritsky, P., Basalova, N., Eremichev, R., Milovskaya, I., Kulebyakin, K., Kulebyakina, M., Rodionov, S., Omelyanenko, N., et al. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.555378 · Cited by 106 · see citing works
Loreti, M., & Sacco, A. (2022) · npj Regenerative Medicine · doi:10.1038/s41536-022-00204-z · Cited by 101 · see citing works
Gattazzo, F., Laurent, B., Relaix, F., Rouard, H., & Didier, N. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.07.011 · Cited by 93 · see citing works
“In addition, we used fluorescence-activated cell sorting (FACS) to sort cells stained with these coupled antibodies and counterstained them with antibodies commonly used for immunofluorescence (IF) in the field (Figures S2B–S2D; Table S4) (Eliazer et al., 2019; Machado et al., 2017; Paris et al., 2016).”
MethodThe mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells
Baker, N., Wade, S., Triolo, M., Girgis, J., Chwastek, D., Larrigan, S., Feige, P., Fujita, R., Crist, C. G., Rudnicki, M. A., et al. (2022) · Cell stem cell · doi:10.1016/j.stem.2022.07.010 · Cited by 91 · see citing works
Kann, A. P., Hung, M., Wang, W., Nguyen, J., Gilbert, P. M., Wu, Z., & Krauss, R. S. (2022) · Cell stem cell · doi:10.1016/j.stem.2022.04.016 · Cited by 78 · see citing works
Muscle Stem Cell Quiescence: Controlling Stemness by Staying Asleep
Ancel, S., Stuelsatz, P., & Feige, J. N. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2021.02.006 · Cited by 76 · see citing works
Molecular and spatial landmarks of early mouse skin development
Jacob, T., Annusver, K., Czarnewski, P., Dalessandri, T., Kalk, C., Levron, C. L., Sanz, N. C., Kastriti, M. E., Mikkola, M. L., Rendl, M., et al. (2023) · Developmental Cell · doi:10.1016/j.devcel.2023.07.015 · Cited by 74 · see citing works
Contribution of muscle satellite cells to sarcopenia
Huo, F., Liu, Q., & Liu, H. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.892749 · Cited by 74 · see citing works
“Wnt4, another cytokine secreted bymuscle fibers, can delayMuSC entry into the cell cycle and activate Rho-GTPase acting on the cytoskeleton, causing mechanical sclerosis of MuSCs (Eliazer et al., 2019).”
BackgroundThe CalcR-PKA-Yap1 Axis Is Critical for Maintaining Quiescence in Muscle Stem Cells
Zhang, L., Noguchi, Y.-T., Nakayama, H., Kaji, T., Tsujikawa, K., Ikemoto‐Uezumi, M., Uezumi, A., Okada, Y., Doi, T., Watanabe, S., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.10.057 · Cited by 74 · see citing works
Flores‐Opazo, M., Kopinke, D., Helmbacher, F., Fernández‐Verdejo, R., Tuñón‐Suárez, M., Lynch, G. S., & Contreras, O. (2024) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2024.101277 · Cited by 66 · see citing works
“Additionally, muscle fibers actively secrete WNT4A, which helps maintain MuSC quiescence (Eliazer et al., 2019).”
BackgroundStem cell aging in the skeletal muscle: The importance of communication
Hong, X., Campanario, S., Ramírez‐Pardo, I., Grima-Terrén, M., Isern, J., & Muñoz‐Cánoves, P. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101528 · Cited by 69 · see citing works
Fukada, S., Akimoto, T., & Sotiropoulos, A. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2020.118742 · Cited by 65 · see citing works
GLI3 regulates muscle stem cell entry into GAlert and self-renewal
Brun, C. E., Sincennes, M., Lin, A. Y., Hall, D. T., Jarassier, W., Feige, P., Grand, F. L., & Rudnicki, M. A. (2022) · Nature Communications · doi:10.1038/s41467-022-31695-5 · Cited by 55 · see citing works
Anderson, J. E. (2021) · European Journal of Applied Physiology · doi:10.1007/s00421-021-04865-4 · Cited by 52 · see citing works
The cell as matter: Connecting molecular biology to cellular functions
Li, Y., Tang, W., & Guo, M. (2021) · Matter · doi:10.1016/j.matt.2021.03.013 · Cited by 52 · see citing works
Squishy matters – Corneal mechanobiology in health and disease
Thomasy, S. M., Leonard, B. C., Greiner, M. A., Skeie, J. M., & Raghunathan, V. K. (2024) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2023.101234 · Cited by 49 · see citing works
“In other cell types, including mouse mammary gland stromal cells (Lerche et al., 2020), murine incisor stem cells (Otsu et al., 2021), and muscle stem cells (Eliazer et al., 2019).”
BackgroundThe mechanosensitive ion channel PIEZO1 promotes satellite cell function in muscle regeneration
Hirano, K., Tsuchiya, M., Shiomi, A., Takabayashi, S., Suzuki, M., Ishikawa, Y., Kawano, Y., Takabayashi, Y., Nishikawa, K., Nagao, K., et al. (2022) · Life Science Alliance · doi:10.26508/lsa.202201783 · Cited by 47 · see citing works
“Eliazer et al (2019) demonstrated thatmyofibre-derivedWnt4 is essential for the maintenance of stemness in MuSCs through the RhoA-dependent repression of the transcription co-activator YAP1.”
BackgroundStem cell quiescence and its clinical relevance
Luo, M., Li, J.-F., Yang, Q., Zhang, K., Wang, Z., Zheng, S. S., & Zhou, J. (2020) · World Journal of Stem Cells · doi:10.4252/wjsc.v12.i11.1307 · Cited by 47 · see citing works
Moyle, L. A., Cheng, R. Y., Liu, H., Davoudi, S., Ferreira, S. A., Nissar, A. A., Sun, Y., Gentleman, E., Simmons, C. A., & Gilbert, P. M. (2020) · Molecular Biology of the Cell · doi:10.1091/mbc.e20-01-0078 · Cited by 41 · see citing works
“…there is growing evidence that mechanical and biochemical cues at the SC niche act in tandem to guide cell fate (Urciuolo et al. , 2013; Rozo et al. , 2016; Safaee et al. , 2017; Baghdadi et al. , 2018; Eliazer et al. , 2019) (reviewed in Dumont et al. , 2015b; Evano and Tajbakhsh, 2018).”
BackgroundAlbors, A. R., Singer, G. A., Llorens-Bobadilla, E., Frisén, J., May, A. P., Ponting, C. P., & Storey, K. G. (2023) · Developmental Cell · doi:10.1016/j.devcel.2023.01.003 · Cited by 43 · see citing works
The biophysical property of the limbal niche maintains stemness through YAP
Bhattacharya, S., Mukherjee, A., Pisano, S., Dimri, S., Knaane, E., Altshuler, A., Nasser, W., Dey, S., Shi, L., Mizrahi, I., et al. (2023) · Cell Death and Differentiation · doi:10.1038/s41418-023-01156-7 · Cited by 38 · see citing works
“However, in a few recent studies, mouse mammary gland stromal fibroblasts [16], murine incisor SCs [17], and muscle SCs [18] show opposite responses of YAP localization to matrix stiffness or mechanotransduction stimulation by the Rho-A pathway.”
BackgroundWNT Signaling in Stem Cells: A Look into the Non-Canonical Pathway
Sarabia-Sánchez, M. Á., & Robles‐Flores, M. (2023) · Stem Cell Reviews and Reports · doi:10.1007/s12015-023-10610-5 · Cited by 43 · see citing works
Regenerating human skeletal muscle forms an emerging niche in vivo to support PAX7 cells
Hicks, M. R., Saleh, K. K., Clock, B., Gibbs, D. E., Yang, M., Younesi, S., Gane, L., Gutierrez-Garcia, V., Xi, H., & Pyle, A. D. (2023) · Nature Cell Biology · doi:10.1038/s41556-023-01271-0 · Cited by 40 · see citing works
“Regulation of the mouse Pax7 cell number set point has been demonstrated via Wnt4 knockdown 72 , and increasing the SC number set point could have exciting implications for muscle regeneration and establishing niches from hPSCs.”
Tissue cross talks governing limb muscle development and regeneration
Helmbacher, F., & Stricker, S. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.05.005 · Cited by 39 · see citing works
“quiescent state, interestingly involving repression of YAP [181].”
BackgroundLi, M., Rao, X., Cui, Y., Zhang, L., Li, X., Wang, B., Zheng, Y., Teng, L., Zhou, T., & Zhuo, W. (2021) · Oncogene · doi:10.1038/s41388-021-02119-3 · Cited by 38 · see citing works
“Factors that activate RHOA include: mechanical cues [51], GPCR agonist [28], Wnt4 [74], mevalonate [75, 76], etc. Active RHOA induce a robust YAP dephosphorylation by facilitating F-actin polymerization.”
BackgroundThe muscle stem cell niche at a glance
Hung, M., Lo, H.-F., Jones, G. E. L., & Krauss, R. S. (2023) · Journal of Cell Science · doi:10.1242/jcs.261200 · Cited by 34 · see citing works
Madl, C. M., Wang, Y. X., Holbrook, C. A., Su, S., Shi, X., Byfield, F. J., Wicki, G., Flaig, I. A., & Blau, H. M. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2406787121 · Cited by 33 · see citing works
“To probe which mechanosensitive pathways are implicated in the observed differences in cell morphology and mechanical memory acquisition, we assayed for the activity of three pathways known to play a role in myogenic progression: Rho and Rac GTPases and YAP ( 21 , 33 , 35 , 36 ).”
Fukada, S., & Ito, N. (2021) · Experimental Cell Research · doi:10.1016/j.yexcr.2021.112907 · Cited by 31 · see citing works
Eliazer, S., Sun, X., Barruet, E., & Brack, A. S. (2022) · eLife · doi:10.7554/elife.68180 · Cited by 33 · see citing works
“The multinucleated muscle fiber functions as a niche cell for the SC, regulating the depth of quiescence and rate of activation in response to injury ( Eliazer et al., 2019 ).”
InfluentialSelf-citationRho GTPases in Skeletal Muscle Development and Homeostasis
Rodríguez‐Fdez, S., & Bustelo, X. R. (2021) · Cells · doi:10.3390/cells10112984 · Cited by 31 · see citing works
“This activation is thought to occur through a non-canonical Wnt signaling pathway, first identified during gastrulation, that requires the Frizzled/Dishevelled 2-mediated stimulation of Dishevelled-associated activator of morphogenesis 1 (Daam1) [92,93].”
BackgroundMitogen signaling strength and duration can control cell cycle decisions
Nussinov, R., Zhang, W., Liu, Y., & Jang, H. (2024) · Science Advances · doi:10.1126/sciadv.adm9211 · Cited by 31 · see citing works
“Wnt4 activates RhoA in quiescent stem cells to maintain mechanical strain ( 46 ).”
Price, F. D., Matyas, M. N., Gehrke, A. R., Chen, W., Wolin, E., Holton, K. M., Gibbs, R. M., Lee, A. E., Singu, P. S., Sakakeeny, J. S., et al. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02344-7 · Cited by 30 · see citing works
“3b) 4,99 .”
Skeletal muscle aging – Stem cells in the spotlight
Henze, H., Jung, M. J., Ahrens, H. E., Steiner, S., & von Maltzahn, J. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111283 · Cited by 28 · see citing works
“Wnt signaling plays an important role in MuSC function, further underscored by a recent study that demonstrated that Wnt4 generated in the myofiber maintains MuSC quiescence through RhoA (Eliazer et al., 2019).”
Cipriano, A., Macino, M., Buonaiuto, G., Santini, T., Biferali, B., Peruzzi, G., Colantoni, A., Mozzetta, C., & Ballarino, M. (2021) · eLife · doi:10.7554/elife.54782 · Cited by 29 · see citing works
“In the muscle stem cell niche, WNT signalling is key in coordinating MuSC transitions from quiescence, proliferation, commitment, and differentiation (Brack et al., 2008; Eliazer et al., 2019; Lacour et al., 2017; Le Grand et al., 2009; Parisi et al., 2015; Rudolf et al., 2016).”
BackgroundRegulation of muscle stem cell fate
Fu, X., Zhuang, C., & Hu, P. (2022) · Cell Regeneration · doi:10.1186/s13619-022-00142-7 · Cited by 30 · see citing works
Henze, H., Hüttner, S. S., Koch, P., Schüler, S. C., Groth, M., von Eyß, B., & von Maltzahn, J. (2024) · npj Regenerative Medicine · doi:10.1038/s41536-024-00353-3 · Cited by 28 · see citing works
Three‐dimensional chromatin re‐organization during muscle stem cell aging
Yang, B. A., Larouche, J. A., Sabin, K., Fraczek, P. M., Parker, S. C. J., & Aguilar, C. A. (2023) · Aging Cell · doi:10.1111/acel.13789 · Cited by 26 · see citing works
Ma, H., Xing, F., Yu, P., Xu, J., Wu, X., Luo, R., Xiang, Z., Rommens, P. M., Duan, X., & Ritz, U. (2023) · Materials & Design · doi:10.1016/j.matdes.2023.111591 · Cited by 27 · see citing works
Neirijnck, Y., Sararols, P., Kühne, F., Mayère, C., Arachchige, L. C. W., Regard, V., Nef, S., & Schedl, A. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112191 · Cited by 27 · see citing works
Li, N., Chen, Y., Wang, Q., Liu, X., Han, C., Qu, C., Guan, X., Zou, W., Wang, X., Li, A., et al. (2025) · Stem Cell Research & Therapy · doi:10.1186/s13287-025-04481-5 · Cited by 24 · see citing works
“These pathways regulate SCs quiescence, proliferation, and differentiation by modulating cytoskeletal dynamics and transcriptional programs [52, 53].”
Sénéchal, C., Fujita, R., Jamet, S., Maïga, A., Dort, J., Orfi, Z., Dumont, N. A., Bouvier, M., & Crist, C. G. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111645 · Cited by 23 · see citing works
Molecular regulation of satellite cells via intercellular signaling
Yeh, C.-J., Sattler, K. M., & Lepper, C. (2023) · Gene · doi:10.1016/j.gene.2023.147172 · Cited by 21 · see citing works
Molecular clocks, satellite cells, and skeletal muscle regeneration
Kahn, R. E., Dayanidhi, S., Lacham‐Kaplan, O., & Hawley, J. A. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00073.2023 · Cited by 23 · see citing works
Yue, F., Gu, L., Qiu, J., Oprescu, S. N., Beckett, L. M., Ellis, J. M., Donkin, S. S., & Kuang, S. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00397-1 · Cited by 23 · see citing works
“…such as Notch (Baghdadi et al, 2018; Bjornson et al, 2012; Mourikis et al, 2012; Verma et al, 2018; Wen et al, 2012), Wnt (Brack et al, 2007; Eliazer et al, 2019; Le Grand et al, 2009), p38/MAPK (Troy et al, 2012) and components of the extracellular matrix (Chang et al, 2018; Dumont et al,…”
Kim, I., Ghosh, A., Bundschuh, N., Hinte, L. C., Petrosyan, E., von Meyenn, F., & Bar‐Nur, O. (2022) · Science Advances · doi:10.1126/sciadv.abj4928 · Cited by 24 · see citing works
Jacques, E., Kuang, Y., Kann, A. P., Grand, F. L., Krauss, R. S., & Gilbert, P. M. (2022) · eLife · doi:10.7554/elife.81738 · Cited by 21 · see citing works
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“In addition, previous studies have proven that mediation of RhoA regulates proliferation and differentiation of mesenchymal stem cells [26–29], adipose-derived stem cells (ADSCs) [30], muscle stem cells [31], and a bulk of cancer cells [18, 32, 33].”
BackgroundIsolation of muscle stem cells from rat skeletal muscles
Sesillo, F. B., Wong, M., Cortez, A., & Alperin, M. (2019) · Stem Cell Research · doi:10.1016/j.scr.2019.101684 · Cited by 21 · see citing works
“1) (Parisi et al., 2015; Eliazer et al., 2019; Schaaf et al., 2018).”
Muscle stem cells get a new look: Dynamic cellular projections as sensors of the stem cell niche
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Autophagy in adult stem cell homeostasis, aging, and disease therapy
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“This cytoprotective mechanism enables quiescent SCs to preserve their stemness and maintain the integrity of the SC pool, thereby supporting long-term tissue homeosta - sis (Eliazer 2019).”
Regenerative medicine for male infertility: A focus on stem cell niche injury models
Sagaradze, G. D., Monakova, A., Basalova, N. A., Popov, V. S., Balabanyan, V. Y., & Efimenko, A. Y. (2022) · Biomedical Journal · doi:10.1016/j.bj.2022.01.015 · Cited by 20 · see citing works
“[38] Eliazer S, Muncie JM, Christensen J, Sun X, D'Urso RS, Weaver VM, et al.”
BackgroundMuscle stem cell adaptations to cellular and environmental stress
Gugliuzza, M. V., & Crist, C. G. (2022) · Skeletal Muscle · doi:10.1186/s13395-022-00289-6 · Cited by 20 · see citing works
“In response to injury, the earliest stages of MuSC activation include the rapid dissociation of RNA granules and the accumulation of MYF5 and MYOD protein [2, 7, 9, 10].”
BackgroundMcCourt, J. L., Stearns-Reider, K. M., Mamsa, H., Kannan, P., Afsharinia, M. H., Shu, C., Gibbs, E. M., Shin, K. M., Kurmangaliyev, Y. Z., Schmitt, L. R., et al. (2023) · Skeletal Muscle · doi:10.1186/s13395-022-00311-x · Cited by 19 · see citing works
The cell in the age of the genomic revolution: Cell Regulatory Networks
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A Long Journey before Cycling: Regulation of Quiescence Exit in Adult Muscle Satellite Cells
Zhou, S., Han, L., & Wu, Z. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031748 · Cited by 18 · see citing works
“Interestingly, myofiber derived WNT4 promotes MuSC quiescence by activating non-canonical RhoA-YAP signaling and restricting MuSC migration [107].”
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“In the regenerative niche of muscle fibers, a Wnt4-Rho signaling axis is recently found to constrain satellite cell numbers and their activation, while RhoA disruption is essential for muscle stem cell activation [51].”
BackgroundZhong, P., Li, X., & Li, J. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1551561 · Cited by 18 · see citing works
Saclier, M., Angelini, G., Bonfanti, C., Mura, G., Temponi, G., & Messina, G. (2022) · The Journal of Pathology · doi:10.1002/path.5895 · Cited by 16 · see citing works
“In our twomurine models, ROCK inhibition did not modify the number of SCs expressing Nfix, but we observed a decrease in the number of SCs per mm(2) that is consistent with previous studies [56,57].”
BackgroundResultCORP: Using transgenic mice to study skeletal muscle physiology
Mobley, C. B., Vechetti, I. J., Valentino, T. R., & McCarthy, J. J. (2020) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00021.2020 · Cited by 16 · see citing works
Metabolic regulation in adult and aging skeletal muscle stem cellsPreprint
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“In muscle fibers, PR favors muscle regeneration by indirectly activating MuSCs through reduced expression of myofiber Wnt4 (Wang et al. 2021), which physiologically maintains MuSC quiescence (Eliazer et al. 2019).”
Post-natal muscle growth and protein turnover: a narrative review of current understanding
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“Recently, a study reported that Wnt4 produced by muscle fibers maintains muscle stem cell quiescence through RhoA [41].”
BackgroundWe need to talk—how muscle stem cells communicate
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The extracellular matrix niche of muscle stem cells
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RhoA-mediated G12-G13 signaling maintains muscle stem cell quiescence and prevents stem cell loss
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“The Primers used for genotyping are shown in Supplementary Table S2.”
BackgroundMethodInfluentialAging: A struggle for beneficial to overcome negative factors made by muscle and bone
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Regulation of the Wnt signaling pathway during myogenesis by the mammalian SWI/SNF ATPase BRG1
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“The role of extracellular matrix-dependent signaling pathways is linked to the mechano-contractile nature of the skeletal muscle tissue (Eliazer et al., 2019).”
InfluentialDlk1 regulates quiescence in calcitonin receptor-mutant muscle stem cells
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Plasticity of muscle stem cells in homeostasis and aging
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Togninalli, M., Ho, A. T. V., Madl, C. M., Holbrook, C. A., Wang, Y. X., Magnusson, K. E. G., Kirillova, A., Chang, A. C. H., & Blau, H. M. (2023) · npj Regenerative Medicine · doi:10.1038/s41536-023-00277-4 · Cited by 9 · see citing works
“Secreted paracrine signals from the niche including Wnt4, vascular endothelial growth factor (VEGF), and oncostatin M (OSM) have also been implicated in maintaining MuSC quiescence 7 – 9 .”
Native collagen VI delays early muscle stem cell differentiation
Metti, S., Ros, F. D., Toniato, G., Cescon, M., & Bonaldo, P. (2024) · Journal of Cell Science · doi:10.1242/jcs.261419 · Cited by 9 · see citing works
Biology of Hippo signaling pathway: Skeletal muscle development and beyond
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Organ‐Specific Dedifferentiation and Epigenetic Remodeling in In Vivo Reprogramming
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Regulation of muscle stem cell function
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“Its injury-induced downregulation serves as a key permissive signal for initiating the regeneration program [38].”
Overcoming muscle stem cell aging
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Satellite cell-derived TRIM28 is pivotal for mechanical load- and injury-induced myogenesis
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“Speci fi cally, in mature skeletal muscle, satellite cells are quiescent but they can be activated by stimuli such as an increase in mechanical loading or injury (Eliazer et al, 2019; Murach et al, 2021).”
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“Relative gene expression was normalized with the housekeeping gene ef1-a and analyzed by the comparative 2 method (37).”
MethodBrondolin, M., Herzog, D., Sultan, S. H. A., Warburton, F. G., Vigilante, A., & Knight, R. D. (2023) · Open Biology · doi:10.1098/rsob.230037 · Cited by 5 · see citing works
“In quiescent muSCs, force induced activation of RhoA via Wnt4 signalling acts to repress Yap activity so preventing muSC activation [36].”
BackgroundWhat is the nature of stem cells? A unified dispositional framework
Suárez, J. (2023) · Biology & Philosophy · doi:10.1007/s10539-023-09930-0 · Cited by 6 · see citing works
“Eliazer et al (2019) provide a good example where stemness can be manipulated by masking the disposition in a way that alters the first causal step in Cproc.”
BackgroundLin, K., Liu, J., Tse, E. H. Y., Yin, Y., Chan, I. T. C., Dong, A., Ngan, L. P., & Cheung, T. H. (2025) · Stem Cell Reports · doi:10.1016/j.stemcr.2025.102745 · Cited by 6 · see citing works
- Authors
- Eliazer, S., Muncie, J. M., Christensen, J., Sun, X., D’Urso, R. S., Weaver, V. M., & Brack, A. S.
- Affiliations
- University of California, San Francisco (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Brack, Andrew S.
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 25
- Issue
- 5
- Pages
- 654-665.e4
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC6842437
- OpenAlex
- W2971702444
- Cited by
- 171
- References
- 73
- Citations by year
- 2026: 18 · 2025: 23 · 2024: 27 · 2023: 32 · 2022: 22 · 2021: 24 · 2020: 21 · 2019: 3 · 2013: 1
- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- Wnt4, satellite cells, muscle stem cells, quiescence, RhoA, YAP, mechanical strain, cytoskeleton signaling, muscle repair, cell cycle entry, tissue homeostasis, paracrine signaling
- MeSH terms
- YAP-Signaling Proteins, Animals, Cytoskeleton, Mice, Inbred C57BL, Mice, Transgenic, Regeneration, Signal Transduction, Muscle, Skeletal, Muscle Fibers, Skeletal, Microscopy, Atomic Force, Cell Cycle Proteins, Oligonucleotide Array Sequence Analysis, rhoA GTP-Binding Protein, Satellite Cells, Skeletal Muscle, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Stem Cell Niche, Wnt4 Protein
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