Induced Pluripotent Stem (iPS) Cells Repair and Regenerate Infarcted Myocardium

Abstract

Cardiac myocyte differentiation reported thus far is from iPS cells generated from mouse and human fibroblasts. However, there is no article on the generation of iPS cells from cardiac ventricular specific cell types such as H9c2 cells. Therefore, whether transduced H9c2 cells, originally isolated from embryonic cardiac ventricular tissue, will be able to generate iPS cells and have the potential to repair and regenerate infarcted myocardium remains completely elusive. We transduced H9c2 cells with four stemness factors, Oct3/4, Sox2, Klf4, and c-Myc, and successfully reprogrammed them into iPS cells. These iPS cells were able to differentiate into beating cardiac myocytes and positively stained for cardiac specific sarcomeric α-actin and myosin heavy chain proteins. Following transplantation in the infarcted myocardium, there were newly differentiated cardiac myocytes and formation of gap junction proteins at 2 weeks post-myocardial infarction (MI), suggesting newly formed cardiac myocytes were integrated into the native myocardium. Furthermore, transplanted iPS cells significantly (p < 0.05) inhibited apoptosis and fibrosis and improved cardiac function compared with MI and MI+H9c2 cell groups. Moreover, our iPS cell derived cardiac myocyte differentiation in vitro and in vivo was comparable to embryonic stem cells in the present study. In conclusion we report for the first time that we have H9c2 cell-derived iPS cells which contain the potential to differentiate into cardiac myocytes in the cell culture system and repair and regenerate infarcted myocardium with improved cardiac function in vivo.

Real-Time Force and Frequency Analysis of Engineered Human Heart Tissue Derived from Induced Pluripotent Stem Cells Using Magnetic Sensing

“…uman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for developing cardiac therapies, [1][2][3][4][5][6][7] modeling cardiac development or disease, [7][8][9][10][11] and screening new drugs for efficacy or cardiotoxicity. 8,9,12,13 By studying hiPSC-CMs in engineered heart tissues, which are three-dimensional tissue constructs comprised of cardiomyocytes in a hydrogel, hiPSC-CMs show a more mature phenotype than two-dimensional cultured cardiomyocytes.…”

Stem cells in three-dimensional bioprinting: Future perspectives

“…These cells were then differentiated into cardiomyocytes. This study showed that regeneration of heart tissue after a myocardial infarction was possible using cardiomyocytes differentiated from iPSC (18).…”

“…Fibroblasts and adipose tissue are commonly used to create iPSCs; however, somatic cells can be taken from anywhere in the body. Singla et al (18) showed the first successful transformation of H9C2 cells, also known as cardiomyoblasts, into iPSCs using the transcription factors mentioned previously. These cells were then differentiated into cardiomyocytes.…”

Inhibition of DNA Topoisomerase II Selectively Reduces the Threat of Tumorigenicity Following Induced Pluripotent Stem Cell-Based Myocardial Therapy

“…Our strategies to limit teratoma formation could have been augmented with updated differentiation protocols that yield a greater percentage of cardiac-lineage specification. Previous studies have shown that while intramyocardial transplantation of undifferentiated rat iPSCs resulted in tumorigenesis in the heart [33], terminally differentiated iPSC-derived human cardiomyocytes have significantly improved cardiac function after ischemic cardiomyopathy [33,34]. Additionally, embryonic stem cells have been differentiated to cardiomyocytes and transplanted to form stable intracardiac grafts [35], providing evidence for similar cardiac repair with iPSC-based therapy.…”