Two decades of hopes and failures in search for next generation therapeutics of cardiovascular diseases, is coming to an end by approaching 2021. The beginning of 21st century was coincided with a burst of hopes toward introduction of novel cell-based therapies for damaged myocardium. Therapeutics which could surpass the intermittent satisfactory reflow and/or revascularization therapies. By far, one can subdivide such preclinical attempts and clinical trials into two categories; those attempted repair and those aimed regeneration.1,2 The bone-marrow derived cells including unfractionated cells or mesenchymal stem cells could reside in the first category along with skeletal myoblasts and adipose-derived cells. Although these cells have not undergone trans-differentiation into cardiomyocytes after transplantation, but could improve cardiac function through their high secretory profile and mostly by immunomodulatory and proangiogenic effects.2 This can explain their promising impacts, despite extremely low engraftment degree 3 or other possible issues such as ageing and host tissue response. Thus, these sorts of cell therapy could have just been an adjuvant to the common reperfusion or coronary bypass graft procedures.1 In the context of regeneration as the second category, however, scientific community hoped to have the privilege of remuscularizing damaged myocardium. This attempt has started by using cKIT+ cells as the resident progenitor cells of the heart as well as cardiosphere-derived cells.2 However, lineage tracing studies showed that cKIT+ cells mainly differentiated into non-myocytes cells of the heart,2,4 disproving their remuscularization capacity. The introduction of in vitro generated human cardiomyocytes from directed differentiation of pluripotent stem cells (hPSC-CM) brought some new hope in the context of remuscularization. While the main goal of this approach was regeneration, concerns on the possible arrhythmogenic events were hindered its application. Bottom-line, this hPSC-CMs are now being tested in a doctor-initiated clinical trial (jRCT2053190081). Clinical trials which were performed for cell therapy of cardiovascular diseases, in general, nor induced considerable cardiac repair, neither regeneration, but just neutral or marginal improvement. Two decades of preclinical experiments and clinical trials, however, taught us to first resolve the following issues before taking any further actions:
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