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Profibrotic COVID-19 subphenotype exhibits enhanced localized ER-dependent HSP47+ expression in cardiac myofibroblasts in situ. J Mol Cell Cardiol 2023 Dec;185:1-12



Pubmed ID




Scopus ID

2-s2.0-85174455933 (requires institutional sign-in at Scopus site)


We recently described a subgroup of autopsied COVID-19 subjects (∼40%), termed 'profibrotic phenotype,' who exhibited clusters of myofibroblasts (Mfbs), which were positive for the collagen-specific chaperone heat shock protein 47 (HSP47+) in situ. This report identifies increased, localized (hot spot restricted) expression of αSMA, COLα1, POSTN and FAP supporting the identity of HSP47+ cells as myofibroblasts and characterizing a profibrotic extracellular matrix (ECM) phenotype. Coupled with increased GRP78 in COVID-19 subjects, these data could reflect induction of the unfolded protein response for mitigation of proteostasis (i.e., protein homeostasis) dysfunction in discrete clusters of cells. ECM shifts in selected COVID-19 subjects occur without significant increases in either global trichrome positive staining or myocardial injury based quantitively on standard H&E scoring. Our findings also suggest distinct mechanism(s) for ECM remodeling in the setting of SARS-CoV-2 infection. The ratio of CD163+/CD68+ cells is increased in hot spots of profibrotic hearts compared with either controls or outside of hot spots in COVID-19 subjects. In sum, matrix remodeling of human COVID-19 hearts in situ is characterized by site-restricted profibrotic mediated (e.g., HSP47+ Mfbs, CD163+ Mφs) modifications in ECM (i.e., COLα1, POSTN, FAP), with a strong correlation between COLα1 and HSP47+cells within hot spots. Given the established associations of viral infection (e.g., human immunodeficiency virus; HIV), myocardial fibrosis and sudden cardiac death, early screening tools (e.g., plasma biomarkers, noninvasive cardiac magnetic resonance imaging) for diagnosis, monitoring and treatment of fibrotic ECM remodeling are warranted for COVID-19 high-risk populations.

Author List

Jacobs ER, Ross GR, Padilla N, Pan AY, Liegl M, Puzyrenko A, Lai S, Dai Q, Uche N, Rubenstein JC, North PE, Ibrahim EH, Sun Y, Felix JC, Rui H, Benjamin IJ


El-Sayed H. Ibrahim PhD Associate Professor in the Radiology department at Medical College of Wisconsin
Paula E. North MD, PhD Professor in the Pathology department at Medical College of Wisconsin
Amy Y. Pan PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Jason C. Rubenstein MD Associate Professor in the Medicine department at Medical College of Wisconsin
Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

HSP47 Heat-Shock Proteins