Nicholas Allen Stahr

Background: Left ventricular (LV) remodeling is a maladaptive structural response to ischemic injury, such as myocardial infarction (MI), and is the leading cause of heart failure worldwide.^1,6 Often, myocardial revascularization is used to restore blood flow to the infarcted tissue via thrombolysis, percutaneous coronary intervention or coronary artery bypass graft surgery. This reperfusion of the tissue reduces the amount of tissue death, however lacks the ability to regenerate functional cardiac tissue. Though there are novel cell based therapies emerging, improvements in tissue viability, delivery and long-term efficacy still needs growth before becoming clinically available.⁷

Objective: In this narrative literature review, mechanisms are investigated through which fibroblasts can reliably differentiate into induced cardiomyocytes by manipulating biochemical and biomechanical properties of a bioscaffold microenvironment.

Search Methods: Utilizing the PubMed database to identify research articles between 2017-2025, the following keywords were used to obtain sourced for this review: “left ventricular remodeling”, “cardiac fibroblast differentiation”, “induced cardiomyocytes”, “cardiac bioscaffold”.

Results: Fibroblasts were reprogrammed into cardiomyocyte-like cells (iCMs) using small molecules (sodium butyrate, ICG-001, retinoic acid; ALL) and transcription factors (GMT), leading to upregulation of GATA4, TBX5, MEF2C, and cTnT expression, with synchronous beating in coculture. An expanded cocktail (GMTHMy/miR-590-ALL), incorporating Hand2, Myocardin, and miR-590, produced similar results in human cardiac fibroblasts.² Human foreskin fibroblasts were reprogrammed into chemically induced cardiac progenitor cells (hciCPCs) using 6C (CHIR99021, A83-01, GSK126, Forskolin, CTPB, AM580) and BACSI. Following intramyocardial injection into infarcted mouse hearts, hciCPCs expressed cTnT and integrated into myocardium, suggesting successful in vivo lineage commitment.³ Mouse fibroblasts seeded in a 3D porcine-derived ECM (HEM) and treated with small molecules exhibited the earliest beating (day 3) and highest cTnT expression among tested ECMs. In infarcted rats, iCMs from 3D HEM reduced cardiac remodeling and injury more effectively than 2D culture-derived cells.⁴ To assess ECM stiffness effects, fibroblasts cultured on 8 kPa hydrogels—closely matching native myocardial elasticity (~10 kPa)—produced the highest number of beating iCMs, with enhanced differentiation linked to suppression of Rho/ROCK, YAP/TAZ, and integrin signaling pathways.⁵ In a Phase 1 clinical trial, implantation of an acellular ECM scaffold (CorMatrix-EXM) in two patients with myocardial injury improved ejection fraction, reduced scar volume, and increased myocardial perfusion 2.9–4.9-fold in grafted regions, without complications. These results support the therapeutic potential of scaffold-based, cell-free cardiac repair strategies.⁸

Conclusion: While not yet available for clinical use, bioscaffolds seeded with small molecule-induced fibroblasts show promise in cardiac tissue engineering. The ability to direct human fibroblasts toward a cardiomyocyte lineage, shown by sustained expression of cardiac markers such as cTnT, offers a compelling, non-genetic alternative for regenerative therapy. These induced cells retain cardiac identity following intramyocardial injection. Their differentiation is further enhanced when cultured on 3D decellularized ECMs that closely mimic native myocardial architecture. The mechanical properties of the ECM, particularly tissue-matched elasticity, facilitate cardiomyocyte-like differentiation by modulating mechanosensitive pathways such as YAP/TAZ. Clinically, implantation of acellular scaffolds in human patients has demonstrated reparative effects without adverse outcomes, validating the safety and utility of ECM-based therapies. Together, these results suggest that combining implantable bioactive scaffolds with small molecule-induced fibroblasts may offer a viable strategy to mitigate LV remodeling and promote myocardial recovery following ischemic injury.

Work Cited:

1.  Bostan MM, Stătescu C, Anghel L, Șerban IL, Cojocaru E, Sascău R. Post-Myocardial Infarction Ventricular Remodeling Biomarkers-The Key Link between Pathophysiology and Clinic. Biomolecules. Nov 23 2020;10(11)doi:10.3390/biom10111587
2. Singh VP, Pinnamaneni JP, Pugazenthi A, et al. Enhanced Generation of Induced Cardiomyocytes Using a Small-Molecule Cocktail to Overcome Barriers to Cardiac Cellular Reprogramming. J Am Heart Assoc. 2020;9(12):e015686. doi:10.1161/JAHA.119.015686
3. Wang J, Gu S, Liu F, et al. Reprogramming of fibroblasts into expandable cardiovascular progenitor cells via small molecules in xeno-free conditions. Nature Biomedical Engineering. 2022/04/01 2022;6(4):403-420. doi:10.1038/s41551-022-00865-7
4. Jin Y, Kim H, Min S, et al. Three-dimensional heart extracellular matrix enhances chemically induced direct cardiac reprogramming. Sci Adv. 2022;8(50):eabn5768. doi:10.1126/sciadv.abn5768
5. Kurotsu S, Sadahiro T, Fujita R, et al. Soft Matrix Promotes Cardiac Reprogramming via Inhibition of YAP/TAZ and Suppression of Fibroblast Signatures. Stem Cell Reports. 2020;15(3):612-628. doi:10.1016/j.stemcr.2020.07.022
6. Leancă SA, Crișu D, Petriș AO, et al. Left Ventricular Remodeling after Myocardial Infarction: From Physiopathology to Treatment. Life (Basel). Jul 24 2022;12(8)doi:10.3390/life12081111
7. Li H, Bao M, Nie Y. Extracellular matrix-based biomaterials for cardiac regeneration and repair. Heart Fail Rev. Sep 2021;26(5):1231-1248. doi:10.1007/s10741-020-09953-9
8. Svystonyuk DA, Mewhort HEM, Hassanabad AF, et al. Acellular bioscaffolds redirect cardiac fibroblasts and promote functional tissue repair in rodents and humans with myocardial injury. Sci Rep. Jun 11 2020;10(1):9459. doi:10.1038/s41598-020-66327-9