Autonomous Extracellular Matrix Remodeling Controls a Progressive Adaptation in Muscle Stem Cell Regenerative Capacity during Development

Abstract

Muscle stem cells (MuSCs) exhibit distinct behavior during successive phases of developmental myogenesis. However, how their transition to adulthood is regulated is poorly understood. Here, we show that fetal MuSCs resist progenitor specification and exhibit altered division dynamics, intrinsic features that are progressively lost postnatally. After transplantation, fetal MuSCs expand more efficiently and contribute to muscle repair. Conversely, niche colonization efficiency increases in adulthood, indicating a balance between muscle growth and stem cell pool repopulation. Gene expression profiling identified several extracellular matrix (ECM) molecules preferentially expressed in fetal MuSCs, including tenascin-C, fibronectin, and collagen VI. Loss-of-function experiments confirmed their essential and stagespecific role in regulating MuSC function. Finally, fetal-derived paracrine factors were able to enhance adult MuSC regenerative potential. Together, these findings demonstrate that MuSCs change the way in which they remodel their microenvironment to direct stem cell behavior and support the unique demands of muscle development or repair.

Regulation and phylogeny of skeletal muscle regeneration

“…These observations were consistent with a previous study showing the increase of regenerative potential of satellite cells following culture on a substrate that recapitulates the rigidity of muscle tissue compared to plastic (≈10kPa) (Gilbert et al, 2010). In addition, extracellular matrix (ECM) proteins are critical components of the MuSC microenvironment and they undergo gradual remodelling from foetal to adult stages, and during ageing (Chakkalakal et al, 2012;Tierney et al, 2016). For example, fibronectin (Fn) is transiently expressed in activated satellite cells (5dpi) (Bentzinger et al, 2013) and it decreases in aged mice (Lukjanenko et al, 2016).…”

Making muscle: skeletal myogenesisin vivoandin vitro

“…Pax7 + cells generated in vitro from mESCs can give rise to both myofibers and Pax7 + satellite cells when grafted in vivo in an mdx mouse model, suggesting that these cells can behave like bona fide satellite cells (Chal et al, 2015). The myofibers differentiated in vitro from mESCs exhibit characteristics of perinatal fibers, suggesting that the associated Pax7 + cells are likely to correspond to perinatal satellite cells (Tierney et al, 2016).…”

Satellite Cell Heterogeneity in Skeletal Muscle Homeostasis

“…The Notch ligand Delta is also present on the myofiber surface and positively regulates this transition [93]. Autonomous ECM remodeling underlies distinct stem cell functionalities observed between fetal satellite cell precursors and their adult counterparts, regulating their regenerative potential in a stage-specific manner [94]. Fetal satellite cell precursors were able to more efficiently contribute to muscle repair but less efficient in colonizing the niche, reflective of their primary responsibilities during development or regeneration and potentially adapted over time via selective processes.…”