Decellularized neonatal cardiac extracellular matrix prevents widespread ventricular remodeling in adult mammals after myocardial infarction

Abstract

Heart disease remains a leading killer in western society and irreversibly impacts the lives of millions of patients annually. While adult mammals do not possess the ability to regenerate functional cardiac tissue, neonatal mammals are capable of robust cardiomyocyte proliferation and regeneration within a week of birth. Given this change in regenerative function through development, the extracellular matrix (ECM) from adult tissues may not be conducive to promoting cardiac regeneration, although conventional ECM therapies rely exclusively on adultderived tissues. Therefore the potential of ECM derived from neonatal mouse hearts (nmECM) to prevent adverse ventricular remodeling in adults was investigated using an in vivo model of acute myocardial infarction (MI). Following a single administration of nmECM, we observed a significant improvement in heart function while adult heart-derived ECM (amECM) did not improve these parameters. Treatment with nmECM limits scar expansion in the left ventricle and *

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

“…Previously reported ECM-derived therapies for MI encompass: (i) the delivery of decellularized cardiac ECM ( Johnson et al, 2014 ; Wang et al, 2019 ), (ii) scaffolds functionalized with ECM-derived proteins or peptides ( Zhang et al, 2019 ), and (iii) biomaterials that mimic the ECM ( Youngblood et al, 2018 ; Yuan et al, 2019 ) and that are able to deliver soluble cytokines/growth factors ( Rufaihah et al, 2017 ), miRNAs ( Bheri and Davis, 2019 ), or cells ( Chakravarti et al, 2018 ).…”

“…An emergent area in cardiac ECM for therapeutic purposes is the exploitation of young ECM as a source of regenerative targets as different findings support that severe changes in the ECM and in fibroblasts may dictate the loss of cardiac regenerative capacity after birth ( Notari et al, 2018 ; Hortells et al, 2019 ). In fact, neonatal cardiac ECM improves myocardial function in vivo , reduces MI-induced fibrosis, and promotes angiogenesis and endothelial cell activity while the adult counterpart showed no beneficial effect ( Wang et al, 2019 ). Consistently, the dystrophin complex protein agrin, whose expression in the heart decreases from P1 to P7, is an important regulator of cardiomyocyte division during the transient neonatal regenerative period ( Bassat et al, 2017 ).…”

Building an Artificial Cardiac Microenvironment: A Focus on the Extracellular Matrix

“…For this reason, tissue-derived biomaterials are increasingly being used to culture both progenitor and differentiated CMs. Different decellularization and recellularization strategies of cardiac tissue or whole heart have been developed, using myocardium originating from rats ( Ott et al, 2008 ; Carvalho et al, 2012 ; Wang et al, 2019 ), porcines ( Singelyn and Christman, 2010 ; Ferng et al, 2017 ; Lee et al, 2017 ), bovines ( Arslan et al, 2018 ), and even humans ( Johnson et al, 2014 ; Sánchez et al, 2015 ; Guyette et al, 2016 ; Masumoto et al, 2016 ; Tang-Quan et al, 2018 ). Interestingly, cardiac progenitor stromal cells, isolated from newborn mice or human fetal heart, can increase their proliferative capacity and expression of key cardiac transcription factors when cultured in a cardiac-derived ECM hydrogel compared to collagen only, both in 2D ( French et al, 2012 ) and 3D ( Gaetani et al, 2016 ).…”

Cardiomyogenesis Modeling Using Pluripotent Stem Cells: The Role of Microenvironmental Signaling

“…This approach leads to distinct possibilities, including the development of new cardiac tissue engineering strategies, through the use of decellularized/recellularized organs in transplants, as well as allowing the characterization of the cardiac ECM in normal or pathological conditions. Over the last 10 years, different decellularization and recellularization strategies were developed and performed with murine (Ott et al, 2008; Carvalho et al, 2012; Lu et al, 2013; Wang et al, 2019), porcine (Ott et al, 2008; Weymann et al, 2014; Ferng et al, 2017; Lee P.-F. et al, 2017), bovine (Arslan et al, 2018) and even human (Sánchez et al, 2015; Garreta et al, 2016; Guyette et al, 2016) heart tissue (revised by Scarrit et al, 2015; Tang-Quan et al, 2018).…”