Abstract
Coronary artery disease is the most common form of cardiovascular diseases, resulting in the loss of cardiomyocytes (CM) at the site of ischemic injury. To compensate for the loss of CMs, cardiac fibroblasts quickly respond to injury and initiate cardiac remodeling in an injured heart. In the remodeling process, cardiac fibroblasts proliferate and differentiate into myofibroblasts, which secrete extracellular matrix to support the intact structure of the heart, and eventually differentiate into matrifibrocytes to form chronic scar tissue. Discovery of direct cardiac reprogramming offers a promising therapeutic strategy to prevent/attenuate this pathologic remodeling and replace the cardiac fibrotic scar with myocardium in situ. Since the first discovery in 2010, many progresses have been made to improve the efficiency and efficacy of reprogramming by understanding the mechanisms and signaling pathways that are activated during direct cardiac reprogramming. Here, we overview the development and recent progresses of direct cardiac reprogramming and discuss future directions in order to translate this promising technology into an effective therapeutic paradigm to reverse cardiac pathological remodeling in an injured heart.
Highlights
Mortality by cardiovascular diseases accounts for 31.5% of all deaths worldwide [1]
There are five major cellular therapy strategies that have been actively investigated in the past few decades for cardiac regenerative medicine: (1) Transplantation of autologous adult stem cells [2,3,4,5], (2) transplantation of embryonic stem cell (ESC)- or induced pluripotent stem cell-derived CMs [6,7,8], (3) activation of endogenous progenitors [9,10,11,12], (4) cell-cycle reentry of adult CMs [13,14,15,16], and (5) direct cell fate reprogramming [17,18,19,20,21]
Many research progresses of direct cardiac reprogramming have been discussed in recently review articles [24,25,26]; in this article, we reviewed the newest discoveries of direct cardiac reprogramming, including cell cycle regulation, chemokine signaling, inflammatory immune signaling, and single-cell RNA-seq findings during reprogramming of induced cardiomyocyte-like cells
Summary
Mortality by cardiovascular diseases accounts for 31.5% of all deaths worldwide [1]. The most common form of heart disease is coronary artery disease where functional cardiomyocytes (CMs) die out in the ischemic area of the heart and are replaced by a fibrotic scar, which leads to the dysfunction of the heart and eventually heart failure. Developing new strategies of cellular therapies offers more accessible options for a broader group of coronary heart patients and prevents a diseased heart from end-stage failure. There are five major cellular therapy strategies that have been actively investigated in the past few decades for cardiac regenerative medicine: (1) Transplantation of autologous adult stem cells [2,3,4,5], (2) transplantation of embryonic stem cell (ESC)- or induced pluripotent stem cell (iPSC)-derived CMs [6,7,8], (3) activation of endogenous progenitors [9,10,11,12], (4) cell-cycle reentry of adult CMs [13,14,15,16], and (5) direct cell fate reprogramming [17,18,19,20,21]. (iCM), and incorporated a new understanding of matrifibrocytes during cardiac fibrotic remodeling to discuss future directions of translating this promising technology into clinical applications
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