Myoscaffolds reveal laminin scarring is detrimental for stem cell function while sarcospan induces compensatory fibrosis

Author:

Stearns-Reider Kristen M.ORCID,Hicks Michael R.,Hammond Katherine G.,Reynolds Joseph C.,Maity Alok,Kurmangaliyev Yerbol Z.,Chin Jesse,Stieg Adam,Geisse Nicholas A.,Hohlbauch Sophia,Kaemmer Stefan,Schmitt Lauren R.,Pham Thanh T.,Yamauchi Ken,Novitch Bennett G.,Wollman Roy,Hansen Kirk C.,Pyle April D.,Crosbie Rachelle H.

Abstract

ABSTRACTWe developed an on-slide decellularization approach to generate acellular extracellular matrix (ECM) scaffolds that can be repopulated with various cell types to interrogate cell-ECM interactions. Using this platform, we investigated whether fibrotic ECM scarring affected human skeletal muscle progenitor cell (SMPC) functions that are essential for myoregeneration. SMPCs exhibited robust adhesion, motility, and differentiation on healthy muscle-derived myoscaffolds. All SPMC interactions with fibrotic myoscaffolds from dystrophic muscle were severely blunted including reduced motility rate and migration. Furthermore, SMPCs were unable to remodel laminin dense fibrotic scars within diseased myoscaffolds. Proteomics and structural analysis revealed that excessive collagen deposition alone is not pathological, and can be compensatory, as revealed by overexpression of sarcospan and its associated ECM receptors in dystrophic muscle. Our in vivo data also supported that ECM remodeling is important for SMPC engraftment and that fibrotic scars may represent one barrier to efficient cell therapy.

Publisher

Cold Spring Harbor Laboratory

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