Abstract
The regenerative effects of cardiac ckit+ stem cells (ckit+CSCs) in acute myocardial infarction (MI) have been studied extensively, but how these cells exert a protective effect on cardiomyocytes is not well known. Growing evidences suggest that in adult stem cells injury triggers inflammatory signaling pathways which control tissue repair and regeneration. Aim of the present study was to determine the mechanisms underlying the cardioprotective effects of ckit+CSCs following transplantation in a murine model of MI.Following isolation and in vitro expansion, cardiac ckit+CSCs were subjected to normoxic and hypoxic conditions and assessed at different time points. These cells adapted to hypoxia as showed by the activation of HIF-1α and the expression of a number of genes, such as VEGF, GLUT1, EPO, HKII and, importantly, of alarmin receptors, such as RAGE, P2X7R, TLR2 and TLR4. Activation of these receptors determined an NFkB-dependent inflammatory and reparative gene response (IRR). Importantly, hypoxic ckit+CSCs increased the secretion of the survival growth factors IGF-1 and HGF. To verify whether activation of the IRR in a hypoxic microenvironment could exert a beneficial effect in vivo, autologous ckit+CSCs were transplanted into mouse heart following MI. Interestingly, transplantation of ckit+CSCs lowered apoptotic rates and induced autophagy in the peri-infarct area; further, it reduced hypertrophy and fibrosis and, most importantly, improved cardiac function.ckit+CSCs are able to adapt to a hypoxic environment and activate an inflammatory and reparative response that could account, at least in part, for a protective effect on stressed cardiomyocytes following transplantation in the infarcted heart.
Highlights
Myocardial infarction (MI) represents a leading cause of morbidity and mortality worldwide [1]. the ongoing therapeutic strategies, represented by prompt reperfusion of the ischemic myocardium, and pharmacological treatments, mainly based on anti-platelet agents, statins, ACE inhibitors and beta blockers [2], have contributed to decrease the mortality of patients, cardiac ischemia-reperfusion (I/R) injury and adverse remodeling still remain the major factors impairing cardiac function and determining an unsatisfactory prognosis [3]
Following isolation and in vitro expansion, cardiac ckit+CSCs were subjected to normoxic and hypoxic conditions and assessed at different time points. These cells adapted to hypoxia as showed by the activation of HIF-1α and the expression of a number of genes, such as VEGF, GLUT1, EPO, HKII and, importantly, of alarmin receptors, such as RAGE, P2X7R, TLR2 and TLR4
The shortage of oxygen and nutrients leads to the death of cardiomyocytes and endothelial cells [5] with the following passive release of endogenous damageassociated molecular pattern molecules (DAMPs), known as alarmins, that activate the local macrophages and promote the recruitment of leukocytes [6]
Summary
Myocardial infarction (MI) represents a leading cause of morbidity and mortality worldwide [1]. the ongoing therapeutic strategies, represented by prompt reperfusion of the ischemic myocardium, and pharmacological treatments, mainly based on anti-platelet agents, statins, ACE inhibitors and beta blockers [2], have contributed to decrease the mortality of patients, cardiac ischemia-reperfusion (I/R) injury and adverse remodeling still remain the major factors impairing cardiac function and determining an unsatisfactory prognosis [3]. In the surviving cardiomyocytes and endothelial cells, as well as in the inflammatory cells, the post-MI hypoxic microenvironment induces the activation of the hypoxia inducible factor 1 alpha (HIF-1 α) [7], allowing the adaptation of these cells to the reduced oxygen level, and promoting the acquisition of an inflammatory reparative phenotype through the expression of a wide range of genes [8,9,10,11], among which the receptors for alarmins [12,13,14,15,16,17]. The binding of the alarmins their receptors determine the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and the expression of hundreds of genes involved in the inflammatory reparative response (IRR) [18] and accountable for the inflammatory cascade observed following the MI [19]. HIF-dependent adaptation and expression of proinflammatory genes has been observed in hypoxic stem cells [20]
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