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

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

doi:10.1038/s41536-023-00287-2

npj Regenerative Medicine (Mar 2023)

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

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

Affiliations

Kristen M. Stearns-Reider: Department of Integrative Biology and Physiology, University of California, Los Angeles
Michael R. Hicks: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles
Katherine G. Hammond: Department of Integrative Biology and Physiology, University of California, Los Angeles
Joseph C. Reynolds: Department of Integrative Biology and Physiology, University of California, Los Angeles
Alok Maity: Department of Integrative Biology and Physiology, University of California, Los Angeles
Yerbol Z. Kurmangaliyev: Institute for Quantitative and Computational Biology, University of California, Los Angeles
Jesse Chin: Department of Integrative Biology and Physiology, University of California, Los Angeles
Adam Z. Stieg: California NanoSystems Institute, University of California, Los Angeles
Nicholas A. Geisse: Curi Bio
Sophia Hohlbauch: Asylum Research, An Oxford Instruments Company
Stefan Kaemmer: Park Systems, 3040 Olcott St
Lauren R. Schmitt: Department of Biochemistry and Molecular Genetics, University of Colorado, Denver
Thanh T. Pham: Department of Biochemistry and Molecular Genetics, University of Colorado, Denver
Ken Yamauchi: Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles
Bennett G. Novitch: Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles
Roy Wollman: Department of Integrative Biology and Physiology, University of California, Los Angeles
Kirk C. Hansen: Department of Biochemistry and Molecular Genetics, University of Colorado, Denver
April D. Pyle: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles
Rachelle H. Crosbie: Department of Integrative Biology and Physiology, University of California, Los Angeles

DOI: https://doi.org/10.1038/s41536-023-00287-2
Journal volume & issue: Vol. 8, no. 1
pp. 1 – 22

Abstract

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Abstract We developed an on-slide decellularization approach to generate acellular extracellular matrix (ECM) myoscaffolds 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.

Published in npj Regenerative Medicine

ISSN: 2057-3995 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Medicine
Website: https://www.nature.com/npjregenmed/

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