Navigating the Crossroads of Cell Therapy and Natural Heart Regeneration

Abstract

Cardiovascular disease remains the leading cause of death worldwide despite significant advances in our understanding of the disease and its treatment. Consequently, the therapeutic potential of cell therapy and induction of natural myocardial regeneration have stimulated a recent surge of research and clinical trials aimed at addressing this challenge. Recent developments in the field have shed new light on the intricate relationship between inflammation and natural regeneration, an intersection that warrants further investigation.

Keywords: angiogenesis; cardiac; cardiac regeneration; cell therapy; heart regeneration; ischemic heart disease; regeneration; stem cells.

FIGURE 1

Extensive Collateral Artery Formation in the Neonatal Mouse Heart 4 days after MI. (A) Experimental design where Cx40CreER-labeled arteries are shown in red. (B) Confocal image of a watershed area from a P2 control heart. The capillary bed (cyan) is fed by left coronary artery (LCA) and right coronary artery (RCA). (C,D) Confocal images (anterior views) of control (C) and myocardial infarction (MI) (D) hearts. Arterial ECs are shown in black. MI induced collateral arteries that connect ligated (lig) branches (brchs) of the LCA with RCA branches across the watershed area (boxed regions). Asterisks indicate the RCA showing through from the posterior heart wall. (E) Schematic of how collateral arteries restore blood flow (arrows) to injured myocardium. Arteries, red; ligation, blue. (F) Some Cx40CreER-labeled collateral arteries contain smooth muscle (white and red arrows). (G,H) Quantification of Cx40CreER-labeled (G) and smooth muscle-covered (H) collateral arteries. Hearts: n = 8 control, n = 12 MI. (I) Collateral arteries were similar in diameter to quaternary (4°) branches. Arteries: n = 24 Cx40⁺, n = 9 αSMA⁺. (J) Collateral arteries were perfused (white and red arrows). Cap, capillaries; P, postnatal; Tam, tamoxifen; EC, endothelial cells; TdTom, tdTomato. Scale bars: (B), 200 μm; (C,D) low magnification, 500 μm; (C,D) boxed region, 200 μm; (F,J), 200 μm. Error bars indicate SD. ^***p ≤ 0.001, ^****p ≤ 0.0001. Adopted from Das et al. (2019).