Human pluripotent stem cell-derived cardiomyocytes as a target platform for paracrine protection by cardiac mesenchymal stromal cells

Abstract

ischemic heart disease remains the foremost cause of death globally, with survivors at risk for subsequent heart failure. Paradoxically, cell therapies to offset cardiomyocyte loss after ischemic injury improve long-term cardiac function despite a lack of durable engraftment. An evolving consensus, inferred preponderantly from non-human models, is that transplanted cells benefit the heart via early paracrine signals. Here, we tested the impact of paracrine signals on human cardiomyocytes, using human pluripotent stem cell-derived cardiomyocytes (hpSc-cMs) as the target of mouse and human cardiac mesenchymal stromal cells (cMSc) with progenitor-like features. in co-culture and conditioned medium studies, cMScs markedly inhibited human cardiomyocyte death. Little or no protection was conferred by mouse tail tip or human skin fibroblasts. Consistent with the results of transcriptomic profiling, functional analyses showed that the cMSC secretome suppressed apoptosis and preserved cardiac mitochondrial transmembrane potential. protection was independent of exosomes under the conditions tested. in mice, injecting cMSc-conditioned media into the infarct border zone reduced apoptotic cardiomyocytes > 70% locally. Thus, hPSC-CMs provide an auspicious, relevant human platform to investigate extracellular signals for cardiac muscle survival, substantiating human cardioprotection by cMScs, and suggesting the cMSc secretome or its components as potential cell-free therapeutic products. The paramount public health burden of ischemic heart disease 1 and the dearth of restorative growth in adult mammalian myocardium have, together, given focus to maintaining cardiomyocyte number as a therapeutic target 2,3. If successful, this would transform the scope of treatment for ischemic heart disease, beyond merely reperfusion to restore coronary flow. Proposed approaches include diverse cell therapies aimed at the generation of new cardiac muscle, by grafting putative precursors such as bone marrow stem cells, heart-derived cardiac progenitor/stem cells, cardiac mesenchymal cells, cardiosphere-derived cells, and established cardiomyocytes made from pluripotent stem cells 2,3. However, the persistence of grafted cells in recipient hearts is brief, at least in the pre-clinical setting where it can be tracked conclusively, leading to a persuasive twofold paradigm shift 4-13. First, therapeutic grafting to supply de novo contractile myocytes themselves is now understood to require alternatives beyond simplistic injections of naked cells, an aspect ripe for biomaterials and tissue engineering

Cardiac regeneration following myocardial infarction: the need for regeneration and a review of cardiac stromal cell populations used for transplantation

“…MicroRNAs are emerging players in cardiomyocyte proliferation and have been shown to modulate it by predominantly targeting components of the Hippo pathway [ 108 ]. For example, microRNA-199a, which promotes cardiomyocyte proliferation by targeting the Hippo pathway regulators TAOK1 and β-TrCP, was found to be expressed in CDC-derived extracellular vesicles [ 60 , 108 , 109 ]. Delivery of the secretome of MSCs or CPCs has been shown to be sufficient to induce cardiac repair following MI [ 60 , 110 , 111 ].…”

“…For example, microRNA-199a, which promotes cardiomyocyte proliferation by targeting the Hippo pathway regulators TAOK1 and β-TrCP, was found to be expressed in CDC-derived extracellular vesicles [ 60 , 108 , 109 ]. Delivery of the secretome of MSCs or CPCs has been shown to be sufficient to induce cardiac repair following MI [ 60 , 110 , 111 ]. For example, administration of exosomes isolated from human CDCs significantly repressed scarring and improved cardiac function in a porcine MI model [ 111 ].…”

“…Fate-mapping studies disputed the endogenous contribution of SCA1 + cells to cardiomyocytes in homeostasis and after MI [ 58 , 59 ], with cardiac SCA1 + cells representing a subset of vascular endothelial cells and having minimal cardiomyogenic potential. The Noseda group suggested renaming this subpopulation as cardiac mesenchymal stromal cells (cMSCs) [ 60 ] and showed that the secretome of these cMSCs suppressed cardiomyocyte apoptosis and preserved mitochondrial transmembrane potential following menadione treatment. In a mouse MI model, injecting cMSC-conditioned media reduced TUNEL+ cardiomyocytes >70% in the infarct border zone.…”

Catalpol Ameliorates Myocardial I/R Injury Through PI3k/Akt/P53 Signaling-mediated Anti-autophagy and Anti-apoptosis

“…Timely restoration of blood perfusion by drug thrombolysis or interventional surgery is the key to the clinical rescue of patients with MI (Pluijmert et al, 2021; Wang et al, 2017). Large parts of studies have revealed that after blood reperfusion, reactive oxygen species (ROS) will be largely released and induce myocardial cell apoptosis and autophagy, thus seriously affecting the prognosis of patients with MI (Arab et al, 2007; Constantinou et al, 2020; Dlamini et al, 2015; Schiattarella & Hill, 2016; Zhang et al, 2017). Either autophagy or apoptosis is a highly regulated biological event that deeply influences tissue homeostasis, development, and disease (Eisenberg-Lerner et al, 2009; Fuchs & Steller, 2011).…”

Activation of PDGFRA signaling contributes to filamin C–related arrhythmogenic cardiomyopathy

“…PDGFRA is a transmembrane tyrosine kinase receptor activated by PDGFA and PDGFC ( 17 , 18 ). During cardiac development, PDGFRA is implicated in a spectrum of physiologic and pathologic processes, including cell growth and survival ( 19 , 20 ), stem cell differentiation ( 16 , 21 ), and migration ( 13 , 22 ). Following development, both alpha and beta cardiac PDGFRs become silent.…”