Abstract
Stem cell therapy could potentially replace damaged heart muscle for regenerative cardiology. We hypothesized that immature cardiovascular progenitors (CVPs) when transplanted into infarcted hearts would electrically synchronized and mature in vivo thus avoiding the occurrence of VTs. In this study, we reported the derivation and applications of hESC-derived CVPs using highly reproducible (R 2 > 0.95) laminin-221 differentiation protocol. The infarction model was created on 3 months old Sus scrofa pigs where we permanently ligated the coronary arteries and intramyocardially transplanted 200 million CVPs. A total of 3 sham, 10 medium control and 10 CVP transplanted pigs were monitored at 4- and 12-weeks post-transplantation. We demonstrated using 10X spatial transcriptomic analysis at 1-week following transplantation the engraftment of the human CVPs into the pig heart. The cells remained viable and proliferated to formed human graft in the infarcted region at 4- and 12-weeks as indicated by IVIS imaging and histology staining. Heart function was analyzed by magnetic resonance imaging (MRI) and revealed overall improvement in left ventricular ejection fraction by 21.35 ± 3.3 %, which was accompanied by significant improvements in ventricular wall thickness and wall motion, as well as a reduction in infarction size after CVP transplantation as compared to medium control pigs (P < 0.05). Electrophysiology analyses revealed electrical propagation between transplanted cells and host tissue CMs. Temporary episodes of VT over a period of 25 days were developed in 4 out of 10 CVP transplanted pigs and 1 pig had persistent VT, while the rest (n = 5) remained in normal sinus rhythm. All ten pigs survived the experiment without any VT-related death. Finally, computerized tomography (CT) scans revealed no tumor formation after 12-weeks transplantation indicating the long-term safety of the treatment. In conclusion, we reported the generation of an effective and potent CVPs and a significant reduction (50 %) in graft induced VT as compared to studies transplanted with contracting cardiomyocytes. This method may pave the way for stem cell therapy of myocardial infarction in humans.
Published Version
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