Synthetic sulfonyl-hydrazone-1 positively regulates cardiomyogenic microRNA expression and cardiomyocyte differentiation of induced pluripotent stem cells

Abstract

Induced pluripotent stem cells (iPSCs) are obtained from adult cells through overexpression of pluripotency factors. iPSCs share many features with embryonic stem cells (ESCs), circumventing ethical issues, and, noteworthy, match donor's genotype. iPSCs represent therefore a valuable tool for regenerative medicine. Cardiac differentiation of ESCs can be enhanced via microRNAs (miRNAs) and small chemical compounds, which probably act as chromatin remodelers. Cardiomyogenic potential of iPSCs is currently intensely investigated for cell therapy or in vitro drug screening and disease modeling. However, influences of small compounds on iPSC-related cardiomyogenesis have not yet been investigated in details. Here, we compared the effects of two small molecules, bis-peroxo-vanadium (bpV) and sulfonyl-hydrazone-1 (SHZ) at varying concentrations, during cardiac differentiation of murine iPSCs. SHZ (5 µM) enhanced specific marker expression and cardiomyocyte yield, without loss of cell viability. In contrast, bpV showed negligible effects on cardiac differentiation rate and appeared to induce Casp3-dependent apoptosis in differentiating iPSCs. Furthermore, SHZ-treated iPSCs were able to increase beating foci rate and upregulate early and late cardiomyogenic miRNA expression (miR-1, miR-133a, and miR-208a). Thus, our results demonstrate that small chemical compounds, such as SHZ, can constitute a novel and clinically feasible strategy to improve iPSC-derived cardiac differentiation.

Inhibition of Cardiomyocytes Differentiation of Mouse Embryonic Stem Cells by CD38/cADPR/Ca2+ Signaling Pathway

“…Directed CM specification of ES can be promoted by biological molecules, such as BMP2, activin-A, and BMP4, or by co-culture with an endodermal cell line. Increased CM specification of ES cells can also be enhanced by small biological and non-biological molecules, including sulfonylhydrazone, an inducer of Nkx2.5, and BIO, a GSK-3 inhibitor (2, 8–13). Yet, the efficiency for ES-directed cardiac lineage is still low.…”

A chemical approach to myocardial protection and regeneration

“…Overall, our results indicated SHZ as a suitable molecule to increase in vitro iPSC cardiac differentiation at low concentration. 40 Undoubtedly, it would be really desirable to find small molecules that will replace or increase the efficacy of known differentiating key factors including growth factors, cytokines, and conditioning media, and these results supported the idea that a chemical approach to stem cell differentiation has started to became very effective and suitable, as many small molecules are generally not expensive, available in relatively large quantities and poorly immunogenic. 41 Another interesting perspective for the development of new therapeutic strategies to treat heart failure includes the use of a chemical approach to in situ activate resident cells to regenerate the tissue, without any in vitro amplification steps.…”

Myocardial Reprogramming Medicine: The Development, Application, and Challenge of Induced Pluripotent Stem Cells

“…Small molecules and microRNAs were also reported to improve cardiac differentiation and maturation of iPSCs and ESCs [263,264]. The treatment of ascorbic acid, a small molecule, was also reported to enhance cardiac differentiation and maturation of iPSCs simply, universally, and efficiently [265].…”