Sall4 and Gata4 induce cardiac fibroblast transition towards a partially multipotent state with cardiogenic potential

• Published in: Scientific reports 2024-10, Vol.14 (1), p.24182-16, Article 24182
• Main Authors: Gao, Hong, Pathan, Saliha, Dixon, Beverly R. E. A., Pugazenthi, Aarthi, Mathison, Megumi, Mohamed, Tamer M.A., Rosengart, Todd K., Yang, Jianchang
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/532; 631/80; 692/308; 692/4019; AKT protein; Alkaline phosphatase; Animals; Cardiac regeneration; Cardiomyocytes; Cardiovascular diseases; Cell Differentiation; Cellular Reprogramming; Coronary artery disease; DNA-Binding Proteins; Embryo cells; Embryo fibroblasts; Embryogenesis; Endothelial cells; Epigenetics; Fibroblasts; Fibroblasts - metabolism; GATA4 Transcription Factor - genetics; GATA4 Transcription Factor - metabolism; Heart diseases; Homeobox Protein Nkx-2.5 - genetics; Homeobox Protein Nkx-2.5 - metabolism; Humanities and Social Sciences; Humans; Ischemia; Mice; multidisciplinary; Multipotent Stem Cells - cytology; Multipotent Stem Cells - metabolism; Myocardium - cytology; Myocardium - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Nkx2.5 protein; Oct-4 protein; Oct4; Partial reprogramming; Pluripotency; Protein interaction; Rats; Science; Science (multidisciplinary); Signal Transduction; Sox17; Stem cells; Tissue engineering; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptomics; Wnt protein
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-73975-8

Cardiac cellular fate transition holds remarkable promise for the treatment of ischemic heart disease. We report that overexpressing two transcription factors, Sall4 and Gata4, which play distinct and overlapping roles in both pluripotent stem cell reprogramming and embryonic heart development, induces a fraction of stem-like cells in rodent cardiac fibroblasts that exhibit unlimited ex vivo expandability with clonogenicity. Transcriptomic and phenotypic analyses reveal that around 32 ± 6.4% of the expanding cells express Nkx2.5, while 13 ± 3.6% express Oct4. Activated signaling pathways like PI3K/Akt, Hippo, Wnt, and multiple epigenetic modification enzymes are also detected. Under suitable conditions, these cells demonstrate a high susceptibility to differentiating into cardiomyocyte, endothelial cell, and extracardiac neuron-like cells. The presence of partially pluripotent-like cells is characterized by alkaline phosphatase staining, germ layer marker expression, and tumor formation in injected mice ( n  = 5). Additionally, significant stem-like fate transitions and cardiogenic abilities are induced in human cardiac fibroblasts, but not in rat or human skin fibroblasts. Molecularly, we identify that SALL4 and GATA4 physically interact and synergistically stimulate the promoters of pluripotency genes but repress fibrogenic gene, which correlates with a primitive transition process. Together, this study uncovers a new cardiac regenerative mechanism that could potentially advance therapeutic endeavors and tissue engineering.