Advancements in Induced Pluripotent Stem Cell Technology for Cardiac Regenerative Medicine

Abstract

Cardiovascular diseases remain the leading causes of morbidity and mortality in the developed world. Cellular based cardiac regenerative therapy serves as a potential approach to treating cardiovascular diseases. Although various cellular types have been tested, induced pluripotent stem cells are regarded as a promising cell source for therapy. In this review, we will highlight some of the advances in generating induced pluripotent stem cells and differentiation to cardiac cells. We will also discuss the progress in modeling cardiovascular diseases using induced pluripotent stem cell derived cardiac cells. As we continue to make progress in induced pluripotent stem cell and cardiac differentiation technology, we will become closer to application of cardiac regenerative medicine.

Perspectives of induced pluripotent stem cells for cardiovascular system regeneration

“…21,18 Virus-free reprogramming can be achieved by plasmid transfection, episomal vectors or minicircles, protein delivery, transfection of synthetic modified mRNAs, or the bacteriophage fC31 integrase, which reduce the risk of genomic integration. 17,20 However, reprogramming remains largely an inefficient and non-specific process, with efficiencies of transduced cells becoming fully reprogrammed iPSCs lower than 0.01%. Moreover, safety concerns still represent major challenges for clinical translation.…”

“…One such method makes use of the Cre/loxP excision technology. 20 A different excision approach uses piggyBac (PB) transposons. The PB system is usually composed of a donor plasmid containing the transposon, co-transfected with a helper plasmid expressing the transposase.…”

“…More recently, small molecule-based approaches are indicating to be highly efficient in cardiomyocyte generation from iPSCs. 20 For example, Lian et al demonstrated an efficient and robust generation of cardiomyocytes from multiple hPSC lines solely via small molecule modulation of regulatory elements of Wnt/b-catenin signaling. Investigators suggest that b-catenin is essential for cardiogenesis upon hPSC treatment with activin A and BMP4.…”

“…Combination of growth factors such as activin A, bone morphogenic protein 4 (Bmp4), FGF 2, wingless-type mouse mammary tumor virus integration site family members 3A, and vascular endothelial growth factor (VEGF) have been shown to induce cardiomyocyte differentiation with increased efficiencies. 20 Transit inhibition of BMP signaling very early during differentiation is crucial for cardiogenesis in murine ES cells. Egashira's group suggests that administration of noggin, a BMP antagonist, before the EB formation stage would mimic its transient and strong expression during early gastrulation.…”

“…Organ transplantations, including cardiac transplantation, demand immunosuppressive therapies for a patient's whole life that might cause life-threatening problems such as malignancy and infection. 5,6 Cell therapy for cardiac regeneration has evolved considerably during the last decade from skeletal myoblasts in the early stages to the use of mesenchymal and cardiac progenitor cells (CPCs) and ESCs. [7][8][9] In comparison, ESCs have many advantages due to the highly proliferating and cardiomyogenic potentials, however the further application of ESCs in cardiac tissue engineering is still hampered due to the ethical problem and immune response.…”