Cardiac Regeneration: New Insights Into the Frontier of Ischemic Heart Failure Therapy

Figure 1. Therapeutic strategies for ischemic heart disease. Tan box; Standard of care: Following MI, patients undergo infarct revascularization and begin pharmacotherapy to slow disease progression, but ultimately develop heart failure and progressive fibrosis. Blue box; Cell therapy for heart regeneration: schematic indicating factors that regulate CM proliferation and direct reprogramming of fibroblasts to CMs to regenerate the myocardium following MI. Green boxes indicate environmental, signaling, and genetic factors that promote CM proliferation/fibroblast reprogramming. Red boxes indicate factors that impair these processes. Factors that have conflicting reports regarding their roles in inducing CM proliferation are listed in purple text. Blue text indicates factors that enhance direct reprogramming in human fibroblasts. DDR, DNA damage response; G(H)MT, GATA4, (HAND2), MEF2C, TBX5; CRFVPT(M), CHIR99021, RepSox, Forskolin, Valproic acid, Parnate, TTNPB, (Rolipram).

Figure 2. Fibroblast reprogramming strategies. Purple shaded region: direct iCM reprogramming. GMT/GHMT, GATA4, MEF2C, TBX5/GATA4, HAND2, MEF2C, TBX5; MM3, MYOD transactivation domain—MEF2C fusion protein. Tan shaded region: iCPC reprogramming; OSKM, OCT4, SOX2, KLF4, C-MYC; O+SCFP, OCT4 + SB431542, CHIR99021, Forskolin, and Parnate; CRFVPT(M), CHIR99021, RepSox, Forskolin, Valproic acid, Parnate, TTNPB, and (Rolipram); 9C; CHIR99021, BIX01294, A-83-01, AS8351, SC1, OAC2, Y27632, SU16F, and JNJ10198409. Green shaded region: iPSC reprogramming. C6PFVTD; CHIR99021, 616452, Parnate, Forskolin, Valproic Acid, TTNPB, and DZnep. Red shaded region: cardiac differentiation of pluripotent or multipotent stem cells to generate CMs. Lineage specific markers for each cell type are listed in light brown boxes. Purple text indicates factors that enhance reprogramming of rodent fibroblasts. Blue text indicates factors that enhance reprogramming of human fibroblasts. Signaling pathways that enhance or inhibit reprogramming are depicted in green or red boxes, respectively.

Figure 3. Signaling pathways that influence direct cardiac reprogramming. Green text/arrows indicate pathways that enhance reprogramming. Red text/arrows indicate pathways that negatively regulate reprogramming. Solid lines indicate direct interactions. Dashed lines indicate indirect or hypothesized interactions. G, H, M, T, GATA4, HAND2, MEF2C, TBX5; RA, Retinoic acid; NICD, Notch intracellular domain. Transcriptionally repressive histone marks: Me3; H3K27me3. Ub; H2AK119 ubiquitination. Transcriptionally activating histone marks: Ac, histone acetylation.