A transitional extracellular matrix instructs cell behavior during muscle regeneration

Abstract

Urodele amphibians regenerate appendages through the recruitment of progenitor cells into a blastema that rebuilds the lost tissue. Blastemal formation is accompanied by extensive remodeling of the extracellular matrix. Although this remodeling process is important for appendage regeneration, it is not known whether the remodeled matrix directly influences the generation and behavior of blastemal progenitor cells. By integrating in vivo 3-dimensional spatiotemporal matrix maps with in vitro functional time-lapse imaging, we show that key components of this dynamic matrix, hyaluronic acid, tenascin-C and fibronectin, differentially direct cellular behaviors including DNA synthesis, migration, myotube fragmentation and myoblast fusion. These data indicate that both satellite cells and fragmenting myofibers contribute to the regeneration blastema and that the local extracellular environment provides instructive cues for the regenerative process. The fact that amphibian and mammalian myoblasts exhibit similar responses to various matrices suggests that the ability to sense and respond to regenerative signals is evolutionarily conserved.

The axolotl genome and the evolution of key tissue formation regulators

“…Analysis of published tissue-enriched datasets 28 , combined with regeneration time courses 29,30 and our own transcriptional profiling of 22 tissues, identified five transcripts that are upregulated in the limb blastema (the mass of proliferating cells involved in regenerating the limb) with orthology limited to non-amniote vertebrates (Supplementary Information section 7). One of these protein sequences shows a weak similarity to tectorin, a basement membrane component normally found in the inner ear, consistent with studies that implicate extracellular matrix components with having an important role in limb regeneration 31,32 . Notably, another of these transcripts encodes a Ly6 family member in the urokinase type plasminogen activator surface receptor (uPAR) class.…”

Tissue regeneration after injury in adult zebrafish: The regenerative potential of the caudal fin

“…Tissue regeneration has been previously studied using both amphibian and fish models (Johnson and Weston, 1995;Geraudie and Singer, 1992;Brockes, 1997;Jazwinska et al, 2007;Beck et al, 2009;Contreras et al, 2009;Kragl et al, 2009;Calve et al, 2010). In this study, we examined zebrafish caudal fin regeneration after repeated injuries at different ages.…”

“…This is likely due to reduced progenitor cell proliferation and differentiation (Janzen et al, 2006;Collins et al, 2007;Nave, 2008;Kirschner et al, 2010). While amphibians have long been the central characters employed in studies on tissue or organ regeneration (Brockes, 1997;Beck et al, 2009;Contreras et al, 2009;Kragl et al, 2009;Calve et al, 2010), the zebrafish (Danio rerio) have recently emerged as a new vertebrate model for genetic studies of tissue/ organ regeneration. Like amphibians, zebrafish exhibit an enhanced capability of regenerating adult tissues, which include retina, spinal cord, kidney, heart, and fin (Poss et al, 2000a(Poss et al, ,b, 2002aNechiporuk and Keating, 2002;Nechiporuk et al, 2003;Jazwinska et al, 2007;Schoenebeck et al, 2007;Tsai et al, 2007;Qin et al, 2009;Jopling et al, 2010;Thummel et al, 2010).…”

Mechanisms of urodele limb regeneration

“…Dedifferentiated cells express a more limb bud‐like ECM in which type II collagen synthesis is suppressed, type I collagen synthesis remains the same, and fibronectin, tenascin, and hyaluronate accumulate (Ashahina, Obara, & Yoshizato, 1999; Gulati, Zakewski, & Reddi, 1983; Mescher & Munaim, 1986; Onda, Poulin, Tassava, & Chiu, 1991). A temporary “transitional matrix” has been described during early blastema formation in amputated newt limbs that may facilitate the cellularization of myofibers and sustain dedifferentiation of the resulting mononucleate cells (Calve, Odelberg, & Simon, 2010). …”