How the mechanobiology orchestrates the iterative and reciprocal ECM-cell cross-talk that drives microtissue growth

Abstract

Controlled tissue growth is essential for multicellular life and requires tight spatiotemporal control over cell proliferation and differentiation until reaching homeostasis. As cells synthesize and remodel extracellular matrix, tissue growth processes can only be understood if the reciprocal feedback between cells and their environment is revealed. Using de novo–grown microtissues, we identified crucial actors of the mechanoregulated events, which iteratively orchestrate a sharp transition from tissue growth to maturation, requiring a myofibroblast-to-fibroblast transition. Cellular decision-making occurs when fibronectin fiber tension switches from highly stretched to relaxed, and it requires the transiently up-regulated appearance of tenascin-C and tissue transglutaminase, matrix metalloprotease activity, as well as a switch from α5β1 to α2β1 integrin engagement and epidermal growth factor receptor signaling. As myofibroblasts are associated with wound healing and inflammatory or fibrotic diseases, crucial knowledge needed to advance regenerative strategies or to counter fibrosis and cancer progression has been gained.

Growth factors and mechano-regulated reciprocal crosstalk with extracellular matrix tune the keratocyte–fibroblast/myofibroblast transition

“…Combining our 2D and 3D 35,51 data suggests two things: first, the composition of the ECM overruled soluble factor signaling to exert a defining influence on the (K-)F/M transition in our cell culture models. The biochemically and biophysically complex ECM within these 2D and 3D environments clearly played a more dominant instructive role on myofibroblast transition than exogenously supplemented TGFβ1, in agreement with studies that used decellularized cancer-associated stroma ECM 11 , or decellularized fibroblast-derived microtissues 51 . This is remarkable, since TGFβ1 has historically been viewed as an essential ingredient for myofibroblast transition 37 .…”

“…This situation is most reminiscent of the myofibroblast-promoting environment on planar glass substrates (Fig. 7), in stiff 3D collagen gels 37 , and in the 3D microtissue growth front 35,51 . Between days 60 and 180 after laser ablation surgery, the complex collagen fiber topography of the normal corneal stroma reappeared, with corneal haze, Fn, αSMA and the typical myofibroblast morphology progressively disappearing.…”

“…The decreased enzymatic digestion of collagen fibers under tension 50 further highlights the importance of cell contractility for matrix assembly and stabilization. Vice versa, mechanobiological cues, including highly stretched Fn fibers, were identified as drivers and stabilizers of the myofibroblast phenotype in the growth front of de novo grown microtissues 35,51 .…”

“…6, Supplementary Fig. S14, 35,51 ) suggest that a low Fn/collagen ratio inhibits fibroblast to myofibroblast transition. www.nature.com/scientificreports/ Regarding the potential clinical relevance, key features of the wound healing and tissue regeneration phases following in vivo laser ablation surgery of the anterior corneal stroma in rabbits 1 underline a mechanosensory ECM feedback-induced myofibroblast phenotype reversal.…”

H. pylori‐induced NF‐κB‐PIEZO1‐YAP1‐CTGF axis drives gastric cancer progression and cancer‐associated fibroblast‐mediated tumour microenvironment remodelling

“…These myofibroblast CAFs produce ECM and induce mechanical tension within tumours via cellular contraction. 12,13 However, the interplay between α-SMA + CAFs and PIEZO1 within cancer cells, including its activation mechanism, subsequent signaling pathways, and role in GC microenvironmental alteration, remains to be uncovered.…”