Abstract
Myocardial delivery of human c-kit+ cardiac interstitial cells (hCICs) and human mesenchymal stem cells (hMSCs), an emerging approach for treating the failing heart, has been limited by an incomplete understanding of the effects on host myocardium. This computational study aims to model hCIC and hMSC effects on electrophysiology and calcium cycling of healthy and diseased human cardiomyocytes (hCM), and reveals a possible cardiotherapeutic benefit independent of putative regeneration processes. First, we developed an original hCIC mathematical model with an electrical profile comprised of distinct experimentally identified ion currents. Next, we verified the model by confirming it is representative of published experiments on hCIC whole-cell electrophysiology and on hCIC co-cultures with rodent cardiomyocytes. We then used our model to compare electrophysiological effects of hCICs to other non-excitable cells, as well as clinically relevant hCIC-hMSC combination therapies and fused hCIC-hMSC CardioChimeras. Simulation of direct coupling of hCICs to healthy or failing hCMs through gap junctions led to greater increases in calcium cycling with lesser reductions in action potential duration (APD) compared with hMSCs. Combined coupling of hCICs and hMSCs to healthy or diseased hCMs led to intermediate effects on electrophysiology and calcium cycling compared to individually coupled hCICs or hMSCs. Fused hCIC-hMSC CardioChimeras decreased healthy and diseased hCM APD and calcium transient amplitude compared to individual or combined cell treatments. Finally, to provide a theoretical basis for optimizing cell-based therapies, we randomized populations of 2,500 models incorporating variable hMSC and hCIC interventions and simulated their effects on restoring diseased cardiomyocyte electrophysiology and calcium handling. The permutation simulation predicted the ability to correct abnormal properties of heart failure hCMs in fibrotic, but not non-fibrotic, myocardium. This permutation experiment also predicted paracrine signaling to be a necessary and sufficient mechanism for this correction, counteracting the fibrotic effects while also restoring arrhythmia-related metrics such as upstroke velocity and resting membrane potential. Altogether, our in silico findings suggest anti-fibrotic effects of paracrine signaling are critical to abrogating pathological cardiomyocyte electrophysiology and calcium cycling in fibrotic heart failure, and support further investigation of delivering an optimized cellular secretome as a potential strategy for improving heart failure therapy.
Highlights
Heart failure remains a leading cause of morbidity and mortality in Western countries (Benjamin et al, 2017)
To do so, established equations that capture gating kinetics and maximal fluxes for individual membrane channels were fit to experimental patch-clamp studies (Zhang et al, 2014) of Large Conductance Ca2+-activated K+ channel (IKCa), Inward rectifying K+ channel (IKir), Transient outward K+ channel (Ito), and sodium channel (INa) activity in cultured Human c-kit+ cardiac interstitial cell (hCIC)
We note the difference between sodium currents in hCICs and cardiomyocytes—INa in hCIC is mainly encoded by Nav1.3 and Nav1.6, and is very sensitive to inhibition by TTX in the nanomolar range, whereas human cardiac myocyte INa (Nav1.5) is usually blocked by TTX in the micromolar range (Zhang et al, 2014)
Summary
Heart failure remains a leading cause of morbidity and mortality in Western countries (Benjamin et al, 2017). Treating ischemic cardiomyopathy patients by injecting bone marrow-derived human mesenchymal stem cells (hMSCs) induces angiogenesis and decreases myocardial infarction scar size by 30–50% (Hare et al, 2012; Heldman et al, 2014; Karantalis et al, 2014). Mathiasen et al (2019) showed that 12 months after transendocardial injection of autologous hMSCs into ischemic heart failure patients, there was a significant improvement in left ventricular ejection fraction and quality of life relative to placebo (Bolli and Kahlon, 2020). Other cells tested include c-kit+ cardiac interstitial cells (hCICs); despite recent evidence revealing these cells do not possess regenerative capacity (Li et al, 2018), animal studies have consistently shown that hCICtreatment after acute myocardial infarction can, like hMSCs, beneficially affect left ventricular remodeling and dysfunction (Tang et al, 2016)
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