Acellular bioscaffolds redirect cardiac fibroblasts and promote functional tissue repair in rodents and humans with myocardial injury

Abstract

Coronary heart disease is a leading cause of death. Tissue remodeling and fibrosis results in cardiac pump dysfunction and ischemic heart failure. Cardiac fibroblasts may rebuild damaged tissues when prompted by suitable environmental cues. Here, we use acellular biologic extracellular matrix scaffolds (bioscaffolds) to stimulate pathways of muscle repair and restore tissue function. We show that acellular bioscaffolds with bioinductive properties can redirect cardiac fibroblasts to rebuild microvascular networks and avoid tissue fibrosis. Specifically, when human cardiac fibroblasts are combined with bioactive scaffolds, gene expression is upregulated and paracrine mediators are released that promote vasculogenesis and prevent scarring. We assess these properties in rodents with myocardial infarction and observe bioscaffolds to redirect fibroblasts, reduce tissue fibrosis and prevent maladaptive structural remodeling. Our preclinical data confirms that acellular bioscaffold therapy provides an appropriate microenvironment to stimulate pathways of functional repair. We translate our observations to patients with coronary heart disease by conducting a first-in-human observational cohort study. We show that bioscaffold therapy is associated with improved perfusion of infarcted myocardium, reduced myocardial scar burden, and reverse structural remodeling. We establish that clinical use of acellular bioscaffolds is feasible and offers a new frontier to enhance surgical revascularization of ischemic heart muscle.

Bearing My Heart: The Role of Extracellular Matrix on Cardiac Development, Homeostasis, and Injury Response

“…Decellularized tissues were readily translated into the clinic as surgical scaffolds since ECM molecules are highly preserved across species, permitting the application of allogenic and xenogenic tissue-derived ECM. These applications demonstrated low immunogenicity while promoting specific cell functions ( Wicha et al, 1982 ; Badylak, 2004 ; Gilbert et al, 2006 ; Crapo et al, 2011 ; Svystonyuk et al, 2020 ). Decellularization methodologies have evolved toward whole-organ decellularization by improvements such as the delivery of decellularization agents through the vasculature (perfusion) which promotes clearance of cellular remnants in situ ( Ott et al, 2008 ; Badylak et al, 2011 ).…”

Artificial Scaffolds in Cardiac Tissue Engineering

“…Data from preclinical and clinical evaluation of acellular biologic ECM scaffolds in cardiac pump dysfunction and ischemic heart failure showed reduced fibrotic tissue, improved perfusion of infarcted myocardium, and reverse structural remodeling [ 66 ]. A decellularized pericardial matrix colonized with human viable Wharton’s jelly-derived mesenchymal stromal cells was implanted in patients with non-revascularizable myocardial scars and has shown a reduction in scar mass after three months [ 67 ].…”

Canadian Contributions in Fibroblast Biology

“…Similar to tetrandrine, his group has also demonstrated that the SGLT2 inhibitor empagliflozin converted myofibroblasts into a more quiescent phenotype, inhibiting ECM remodelling and attenuating pro-fibrotic marker expression [ 113 ]. His recent work with acellular bioactive scaffolds has shown that implanting them into the heart in a rat MI model, as well as in humans, can redirect cardiac fibroblasts from a fibrotic to a vasculogenic nature, resulting in improved cardiac function, inhibition of post-MI cardiac remodelling, and improving perfusion of the infarcted heart, providing a tractable clinical means to improve cardiac repair during surgical re-vascularization procedures [ 114 ].…”