Abstract
BackgroundConsidering the impaired function of regenerative cells in myocardial infarction (MI) patients with comorbidities and associated risk factors, cell therapy to enhance the regenerative microenvironment was designed using regeneration-associated cells (RACs), including endothelial progenitor cells (EPCs) and anti-inflammatory cells.MethodsRACs were prepared by quality and quantity control culture of blood mononuclear cells (QQMNCs). Peripheral blood mononuclear cells (PBMNCs) were isolated from Lewis rats and conditioned for 5 days using a medium containing stem cell factors, thrombopoietin, Flt-3 ligand, vascular endothelial growth factor, and interleukin-6 to generate QQMNCs.ResultsA 5.3-fold increase in the definitive colony-forming EPCs and vasculogenic EPCs was observed, in comparison to naïve PBMNCs. QQMNCs were enriched with EPCs (28.9-fold, P<0.0019) and M2 macrophages (160.3-fold, P<0.0002). Genes involved in angiogenesis (angpt1, angpt2, and vegfb), stem/progenitors (c-kit and sca-1), and anti-inflammation (arg-1, erg-2, tgfb, and foxp3) were upregulated in QQMNCs. For in vivo experiments, cells were administered into syngeneic rat models of MI. QQMNC-transplanted group (QQ-Tx) preserved cardiac function and fraction shortening 28 days post-MI in comparison with PBMNCs-transplanted (PB-Tx) (P<0.0001) and Control (P<0.0008) groups. QQ-Tx showed enhanced angiogenesis and reduced interstitial left ventricular fibrosis, along with a decrease in neutrophils and an increase in M2 macrophages in the acute phase of MI. Cell tracing studies revealed that intravenously administered QQMNCs preferentially homed to ischemic tissues via blood circulation. QQ-Tx showed markedly upregulated early cardiac transcriptional cofactors (Nkx2-5, 29.8-fold, and Gata-4, 5.2-fold) as well as c-kit (4.5-fold) while these markers were downregulated in PB-Tx. In QQ-Tx animals, de novo blood vessels formed a “Biological Bypass”, observed macroscopically and microscopically, while PB-Tx and Control-Tx groups showed severe fibrotic adhesion to the surrounding tissues, but no epicardial blood vessels.ConclusionQQMNCs conferred potent angiogenic and anti-inflammatory properties to the regenerative microenvironment, enhancing myocardiogenesis and functional recovery of rat MI hearts.
Highlights
Despite improved pharmacological and surgical interventions, ischemic heart disease (IHD) is the leading cause of premature mortality; since the year 2006, IHD-related mortality has increased by 19% worldwide[1]
QQMNCs were enriched with endothelial progenitor cells (EPCs) (28.9-fold, P
Two decades have passed since the discovery of endothelial progenitor cells (EPCs)[2] and several studies have concluded that in addition to cellular replacement of myocardial loss, EPCs of the hematopoietic stem cell (HSC) line secrete paracrine factors which play an essential role in cell to cell communication and the resolution of inflammation and subsequent recovery[3,4,5]
Summary
Despite improved pharmacological and surgical interventions, ischemic heart disease (IHD) is the leading cause of premature mortality; since the year 2006, IHD-related mortality has increased by 19% worldwide[1]. Two decades have passed since the discovery of endothelial progenitor cells (EPCs)[2] and several studies have concluded that in addition to cellular replacement of myocardial loss, EPCs of the hematopoietic stem cell (HSC) line secrete paracrine factors which play an essential role in cell to cell communication and the resolution of inflammation and subsequent recovery[3,4,5]. These paracrine factors can be released from transplanted cells as proteins or extracellular vesicle cargos, along with non-coding single strand miRNAs, a promising therapeutic tool[6]. Considering the impaired function of regenerative cells in myocardial infarction (MI) patients with comorbidities and associated risk factors, cell therapy to enhance the regenerative microenvironment was designed using regeneration-associated cells (RACs), including endothelial progenitor cells (EPCs) and anti-inflammatory cells
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