Promoting cardiac repair and regeneration

The selection of this newsletter significantly illustrates the two aspects of regenerative or repair therapies for myocardial infarction and heart failure: the paracrine effect on cardiomyocytes cell cycle re-entry, macrophages repair capacity and microenvironment on one side and on the other side, the direct contractile effect of re-muscularisation of the fibrotic scar.

The first article (1) used an immunosuppressed cryoinjured Guinea Pig model that received myocardial injections of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) combined with a cocktail of survival factors. Judiciously, an optogenetic approach switched ON and OFF the contraction of implanted CM and provided ex vivo evidence of the contribution of the grafts to the development of left ventricle pressure. This is the first proof of concept of the direct effect of implanted cell contraction during re-muscularisation of the non-transmural scar.

The following article (2) reviewed the latest advances in cell-based therapy using Mesenchymal Stromal/stem cells (MSC) with a focus on pre-conditioning conditions implemented to foster (i) their biological behaviour following post-cardiac implantation and (ii) their paracrine effect for cardiac repair. Remarkably, the authors provided an extensive list of agents and gene modifications implemented for MSC-based cardiac repair therapy. In addition, booming approaches are mentioned, including MSC-derived exosomes and engineered cardiac patches associating matrices and MSC or hiPCS-derived cardiomyocytes, with an emphasis on the actual clinical trials.

The third article (3)  illustrated in vitro the importance of the interaction of a fibrin matrix and bone marrow cell (BMCs) populations and its importance in fostering the cells’ paracrine activity and capacity to create a regenerative environment. In particular, the fibrin-based matrix primed the BMCs. Their secretomes then educated macrophages and induced a switch in their phenotypes. The educated macrophages were prone to promote cardiac cell proliferation in a paracrine way. Interestingly, proteomics screening revealed top molecules released after biologically active-matrix stimulation, among them Osteopontin (OPN), which is the focus of the following article.

In the fourth study (4), Osteopontin and its cardiac repair capacity were comprehensively studied in vivo and in vitro. The authors isolated neonatal cardiac macrophages present in the myocardium following apical resection or an ischemic event and showed increased secretion of OPN. They demonstrated that ONP stimulates the proliferation of neonatal cardiomyocytes, cardiac MSC and endothelial cells. OPN activated CD44 and YAP nuclear translocation and upregulated cell cycle genes. Next, OPN promotes cardiac repair and functional recovery when injected into infarcted adult mouse hearts. Besides the good side, the bad and ugly ones of ONP are also discussed in the article.

Finally (5), the impactful latest research on factors involved in cardiac repair is illustrated in the fifth selected article. Using a Confetti approach, the authors brilliantly demonstrated that cardiomyocytes proliferate clonally in response to cardiac ischaemia. Although this remains a rare event, the selection of cell cycle re-entry of CM and bioinformatic screening of single-cell RNA sequencing allowed the identification of proliferating CM signatures. The authors incorporated the combination of the selected genes in neonatal CM and identified two molecules showing potency for cardiac repair. The authors provided proof of concept of TMSB4 and PTMA as a promotor of CM proliferation and heart function improvement.