Improving cardiac reprogramming for heart regeneration

Abstract

Purpose of review Cardiovascular disease (CVD) is the leading cause of death in the world today, and the death rate has remained virtually unchanged in the last twenty years (American Heart Association). This severe life threatening disease underscores a critical need for developing novel therapeutic strategies to effectively treat this devastating disease. Cell-based therapy represents an extremely promising approach. Generation of induced cardiomyocytes (iCMs) directly from fibroblasts offers an attractive novel strategy for in situ heart regeneration. Major challenges of iCM reprogramming include the low conversion rate and heterogeneity of the iCMs. This review will summarize the major advancements in improving the iCM reprogramming efficiency and iCM maturation. Recent findings Numerous studies have been published in the past 18 months to describe various strategies for achieving more efficient iCM reprogramming. These strategies are based on our understanding of the molecular mechanisms of cardiogenesis, which include transcriptional networks, signaling pathways, and epigenetic cell fate change. Summary Novel strategies for highly efficient iCM reprogramming will be required for applying iCM reprogramming to patients. Creative and combined methods based on our understanding of cardiogenesis will continue to contribute heavily in the advancement of iCM reprogramming. We are highly optimistic that iCM reprogramming based heart therapy will restore the pumping function of damaged patient hearts.

The role of Kabuki Syndrome genesKMT2DandKDM6Ain development: Analysis in Human sequencing data and compared to mice and zebrafish

“…Cardiac reprogramming and epigenetics have been focused in other publications (Engel & Ardehali, 2018; Ieda et al, 2010; L. Liu, I. Lei, H. Karatas, et al, 2016; Liu, Lei, & Wang, 2016; Monroe et al, 2019). In craniofacial development, we have identified Kat2a and Kat2b as being important in regulating cartilage and bone development in both zebrafish and mice.…”

Strategies and Challenges to Improve Cellular Programming-Based Approaches for Heart Regeneration Therapy

“…Although contributing factors have been identified in mouse cardiac reprogramming, human iCMs reprogramming failed to generate robust beating in vitro, indicating that the majority of reprogrammed cells were neither sufficient nor highly mature. Applying genetic and epigenetic assays such as single-cell RNA sequencing, chromatin assay, lncRNAs, Cas9-based genome editing technology, protein interaction network mapping, metabolite stimulating, and inflammatory response inhibition will all be helpful to investigate the more detailed mechanisms underlying iCM reprogramming and give rise to better reprogramming efficiency and iCM maturation [ 107 , 117 ]. Similar to iPSC-CMs, the optimization of culture microenvironments, including the extracellular matrix, paracrine factors, contractile forces, and electrical currents, also improved the maturation of newly reprogrammed iCMs.…”