Human embryonic stem cell-derived cardiomyocytes survive and mature in the mouse heart and transiently improve function after myocardial infarction

Abstract

Regeneration of the myocardium by transplantation of cardiomyocytes is an emerging therapeutic strategy. Human embryonic stem cells (HESC) form cardiomyocytes readily but until recently at low efficiency, so that preclinical studies on transplantation in animals are only just beginning. Here, we show the results of the first long-term (12 weeks) analysis of the fate of HESC-derived cardiomyocytes transplanted intramyocardially into healthy, immunocompromised (NOD-SCID) mice and in NOD-SCID mice that had undergone myocardial infarction (MI). Transplantation of mixed populations of differentiated HESC containing 20-25% cardiomyocytes in control mice resulted in rapid formation of grafts in which the cardiomyocytes became organized and matured over time and the noncardiomyocyte population was lost. Grafts also formed in mice that had undergone MI. Four weeks after transplantation and MI, this resulted in significant improvement in cardiac function measured by magnetic resonance imaging. However, at 12 weeks, this was not sustained despite graft survival. This suggested that graft size was still limiting despite maturation and organization of the transplanted cells. More generally, the results argued for requiring a minimum of 3 months follow-up in studies claiming to observe improved cardiac function, independent of whether HESC or other (adult) cell types are used for transplantation.

Pluripotent Stem Cells and Their Dynamic Niche

“…Even though iPSCs have been differentiated into a number of cell types including cardiomyocytes [129][130][131][132][133], neurons [134,135], blood [133,136,137] and pancreatic cells [137,138], purities over 95% have not been reported and isolating these cells from a heterogeneous cell population is difficult. Furthermore, ESC-/iPSC-derived cells are mostly immature and whether their stage will affect their clinical performance remains to be investigated in a celland disease-specific manner [108].…”

Stem cell therapy for cardiac disease

“…Although the methods for generating CMs and monitoring engraftment, as well as the number of transplanted CMs, varied between studies, hESC-derived CM transplantation has led to measurable benefit (63)(64)(65). Overall, CM transplantation preserved leftventricular function, attenuated post-MI wall thinning, and even partially remuscularized the infarct region.…”

“…Despite these encouraging results, the cardiac-specific benefits determined from in vivo engraftment studies appear transient. Van Laake et al reported that although cardiac function was improved 4 wk after MI, the functional benefit was no longer significant at 12 wk, even after tripling the number of transplanted CMs in a repeat study (63). These results question the utility of fully differentiated CMs for cardiac repair.…”

Differentiation, Characterization and Applications of Human Embryonic Stem Cell –Derived Cardiomyocytes

“…hESC-CM have been transplanted into healthy myocardium of rodents. The cells were reported to survive, form myocardial tissue and proliferate but they were usually separated from the rodent myocardium by a layer of fibrotic tissue (Laflamme, Gold et al 2005;van Laake, Passier et al 2007). When transplanted to infracted rat or mouse hearts, some beneficial effects for the function of the heart have occurred (Laflamme, Chen et al 2007;van Laake, Passier et al 2007).…”

“…The cells were reported to survive, form myocardial tissue and proliferate but they were usually separated from the rodent myocardium by a layer of fibrotic tissue (Laflamme, Gold et al 2005;van Laake, Passier et al 2007). When transplanted to infracted rat or mouse hearts, some beneficial effects for the function of the heart have occurred (Laflamme, Chen et al 2007;van Laake, Passier et al 2007). However, after longer follow-up period, positive effects were not present anymore (van Laake, Passier et al 2007;van Laake, Passier et al 2008;van Laake, Passier et al 2009).…”