Abstract
BackgroundAlthough patient-sourced cardiac stem cells repair damaged myocardium, the extent to which medical co-morbidities influence cardiac-derived cell products is uncertain. Therefore, we investigated the influence of atherosclerotic risk factors on the regenerative performance of human cardiac explant-derived cells (EDCs).MethodsIn this study, the Long Term Stratification for survivors of acute coronary syndromes model was used to quantify the burden of cardiovascular risk factors within a group of patients with established atherosclerosis. EDCs were cultured from human atrial appendages and injected into immunodeficient mice 7 days post-left coronary ligation. Cytokine arrays and enzyme linked immunoassays were used to determine the release of cytokines by EDCs in vitro, and echocardiography was used to determine regenerative capabilities in vivo.ResultsEDCs sourced from patients with more cardiovascular risk factors demonstrated a negative correlation with production of pro-healing cytokines (such as stromal cell derived factor 1α) and exosomes which had negative effects on the promotion of angiogenesis and chemotaxis. Reductions in exosomes and pro-healing cytokines with accumulating medical co-morbidities were associated with increases in production of the pro-inflammatory cytokine interleukin-6 (IL-6) by EDCs. Increased patient co-morbidities were also correlated with significant attenuation in improvements of left ventricular ejection fraction.ConclusionsThe regenerative performance of the earliest precursor cell population cultured from human explant tissue declines with accumulating medical co-morbidities. This effect is associated with diminished production of pro-cardiogenic cytokines and exosomes while IL-6 is markedly increased. Predictors of cardiac events demonstrated a lower capacity to support angiogenesis and repair injured myocardium in a mouse model of myocardial infarction.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0321-4) contains supplementary material, which is available to authorized users.
Highlights
Patient-sourced cardiac stem cells repair damaged myocardium, the extent to which medical co-morbidities influence cardiac-derived cell products is uncertain
Mayfield et al Stem Cell Research & Therapy (2016) 7:60 salvage, several recent publications using tissue samples sourced from non-transplant patients hint that the regenerative performance of cardiac derived cell products may be impaired by patient co-morbidities [5,6,7,8]
Baseline demographics Thirty-two patients were enrolled in this study [66 % male; age 65 ± 2 years; body mass index (BMI) 28 ± 1 kg/m2, Table 1]
Summary
Patient-sourced cardiac stem cells repair damaged myocardium, the extent to which medical co-morbidities influence cardiac-derived cell products is uncertain. A decade of progress towards understanding cardiac stem cell mediated repair of damaged myocardium has borne fruit with the recent completion of two phase 1 clinical trials [1, 2] Despite this promise, significant hurdles remain before cardiac-derived cell therapy can be effectively translated to the clinic. Mayfield et al Stem Cell Research & Therapy (2016) 7:60 salvage, several recent publications using tissue samples sourced from non-transplant patients hint that the regenerative performance of cardiac derived cell products may be impaired by patient co-morbidities [5,6,7,8] These studies examined only crude surrogate endpoints (such as cell culture numbers and proliferation), without reference to actual myocardial repair or the potential mechanisms underlying cell-mediated cardiac repair. We demonstrated that hyperglycemia may have profound effects on the regenerative performance of cardiac stem cells which prompted us to explore the influence of other comorbidities [9]
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