Cardiac regeneration following myocardial infarction rests with the potential of c-kit+ cardiac progenitor cells (CPCs) to repopulate damaged myocardium. The ability of CPCs to reconstitute the heart is restricted by patient age and disease progression. Increasing CPC proliferation, telomere length, and survival will improve the ability of autologous CPCs to be successful in myocardial regeneration. Prior studies have demonstrated enhancement of myocardial regeneration by engineering CPCs to express Pim-1 kinase, but cellular and molecular mechanisms for Pim-1 mediated effects on CPCs remain obscure. We find CPCs rapidly expand following overexpression of cardioprotective kinase Pim-1 (CPCeP), however increases in mitotic rate are short lived as late passage CPCePs proliferate similar to control CPCs. Telomere elongation consistent with a young phenotype is observed following Pim-1 modification of CPCeP; in addition telomere elongation coincides with increased telomerase expression and activity. Interestingly, telomere length and telomerase activity normalize after several rounds of passaging, consistent with the ability of Pim-1 to transiently increase mitosis without resultant oncogenic transformation. Accelerating mitosis in CPCeP without immortalization represents a novel strategy to expand the CPC population in order to improve their therapeutic efficacy.

Summary Heart failure remains a significant cause of morbidity and mortality following myocardial infarction. Cardiac remuscularization with transplantation of human pluripotent stem cell-derived cardiomyocytes is a promising preclinical therapy to restore function. Recent large animal data, however, have revealed a significant risk of engraftment arrhythmia (EA). Although transient, the risk posed by EA presents a barrier to clinical translation. We hypothesized that clinically approved antiarrhythmic drugs can prevent EA-related mortality as well as suppress tachycardia and arrhythmia burden. This study uses a porcine model to provide proof-of-concept evidence that a combination of amiodarone and ivabradine can effectively suppress EA. None of the nine treated subjects experienced the primary endpoint of cardiac death, unstable EA, or heart failure compared with five out of eight (62.5%) in the control cohort (hazard ratio = 0.00; 95% confidence interval: 0–0.297; p = 0.002). Pharmacologic treatment of EA may be a viable strategy to improve safety and allow further clinical development of cardiac remuscularization therapy.

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Background: Engraftment arrhythmias (EAs) are observed in large animal studies of intramyocardial transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) for myocardial infarction. Although transient, the risk posed by EA presents a barrier to clinical translation. Objectives We hypothesized that clinically approved antiarrhythmic drugs can prevent EA-related mortality as well as suppress tachycardia and arrhythmia burden. Methods: hPSC-CM were transplanted into the infarcted porcine heart by surgical or percutaneous delivery to induce EA. Following a screen of antiarrhythmic agents, a prospective study was conducted to determine the effectiveness of amiodarone plus ivabradine in preventing cardiac death and suppressing EA. Results: EA was observed in all subjects, and amiodarone-ivabradine treatment was well-tolerated. None of the treated subjects experienced the primary endpoint of cardiac death, unstable EA or heart failure compared to 5/8 (62.5%) in the control cohort (hazard ratio 0.00; 95% confidence interval, 0-0.297; p = 0.002). Overall survival including two deaths in the treated cohort from immunosuppression-related infection showed borderline improvement with treatment (hazard ratio 0.21; 95% confidence interval, 0.03-1.01; p = 0.05). Without treatment, peak heart rate averaged 305 +/- 29 beats per min (bpm), whereas in treated subjects peak daily heart rate was significantly restricted to 185+/-9 bpm (p = 0.006). Similarly, treatment reduced peak daily EA burden from 96.8 +/- 2.9% to 76.5 +/- 7.9% (p = 0.003). Antiarrhythmic treatment was safely discontinued after approximately one-month of treatment without recrudescence of arrhythmia. Conclusions: The risk of engraftment arrhythmia following hPSC-CM transplantation can be reduced significantly by combined amiodarone and ivabradine drug therapy.

Background-Crescentic glomeruli are the hallmark finding in rapidly progressive glomerulonephritis (RPGN) and are characterized by disruption and proliferation of the glomerular capsule and an influx of cells into Bowman's space. Pauci-immune type RPGN is identified by a lack of immunoglobulins and immune complexes in the glomerular basement membrane.

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1Background: Despite modern pharmacotherapy, heart failure remains a major medical burden. 2 The heart has a limited regenerative capacity, and bolstering regeneration might represent new 3 therapeutic approaches for heart failure patients. Various progenitor cells in the heart have been 4 proposed to have cardiomyogenic properties, but this evidence is based mostly on cell culture 5 and transplantation studies. One population of interest is characterized by the expression of Stem 6 Cell Antigen-1 (Sca-1). Here we tested the hypothesis that Sca-1 + cells are endogenous 7 progenitors for cardiomyocytes in the adult heart. 8 Methods: We evaluated the innate cardiogenic potential of Sca-1 + cells in vivo by generating a 9 novel mouse model to genetically lineage-trace the fate of Sca-1 expressing cells. This was 1 mCm/+ ). Crossing this mouse line to a Cre-dependent tdTomato reporter line allowed for genetic 1 2 lineage-tracing of endogenous Sca-1 + cells (Sca-1 mCm R26 tdTomato ). The frequency of Sca-1 + 1 3 cardiomyocytes was quantified from dispersed cell preparations and confirmed by in situ 1 4 histology. 1 5 Results: We validated the genetic lineage tracing mouse model in bone marrow and heart. 1 6Unlike previous publications suggesting significant cardiogenic potential, we found that less than 1 7 0.02% of cardiomyocytes per year were derived from Sca-1 + cells in the adult heart under 1 8 homeostatic conditions. At six months after myocardial infarction, we found less than 0.01% of 1 9 cardiomyocytes were derived from Sca-1 + cells. 2 0 Conclusion: Our results show that Sca-1 + cells in the adult heart have minimal cardiogenic 2 1 potential under homeostatic conditions or in response to myocardial infarction. 2 2 2

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