Abstract
BackgroundMyocardial microvascular loss after myocardial infarction (MI) remains a therapeutic challenge. Autologous stem cell therapy was considered as an alternative; however, it has shown modest benefits due to the impairing effects of cardiovascular risk factors on stem cells. Allogenic adipose-derived stem cells (ASCs) may overcome such limitations, and because of their low immunogenicity and paracrine potential may be good candidates for cell therapy. In the present study we investigated the effects of allogenic ASCs and their released products on cardiac rarefaction post MI.MethodsPig subcutaneous adipose tissue ASCs were isolated, expanded and GFP-labeled. ASC angiogenic function was assessed by the in-vivo chick chorioallantoic membrane (CAM) model. Pigs underwent MI induction and 7 days after were randomized to receive: allogenic ASCs (intracoronary infusion); conditioned media (CM; intravenous infusion); ASCs + CM; or PBS/placebo (control). Cardiac damage and function were monitored by 3-T cardiac magnetic resonance imaging upon infusion (baseline CMR) and 1 and 3 weeks thereafter. We assessed in the myocardium: microvessel density; angiogenic markers (CD105, CD31, TF, VEGFR2, VEGFR1, vWF, eNOS, CD62); collagen deposition; and reparative fibrosis (TGFβ/TβRII/collagen). Differential proteomics of ASCs and CM was performed to characterize the ASC protein signature.ResultsCAM indicated a significant ASC proangiogenic capacity. In pigs after MI, only PBS/placebo animals displayed an impaired cardiac function 3 weeks after infusion (p < 0.05 vs baseline). Administration of ASCs + CM significantly enhanced neovessel formation and favored cardiac repair post MI (p < 0.05 vs the other groups). Molecular markers of angiogenesis were significantly upregulated both at transcriptional and protein levels (p < 0.05). The in-silico bioinformatics analysis of the ASC and CM proteome (interactome) indicated activation of a coordinated protein network involved in the formation of microvessels and the resolution of rarefaction.ConclusionCoadministration of allogenic ASCs and their CM synergistically contribute to the neovascularization of the infarcted myocardium through a coordinated upregulation of the proangiogenic protein interactome.
Highlights
Myocardial microvascular loss after myocardial infarction (MI) remains a therapeutic challenge
adipose-derived stem cell (ASC) characterization Flow cytometry demonstrated that cultured swine ASCs were positive for surface markers characteristic of ASCs including CD105 (99 ± 1%), CD29 (78 ± 4%) and CD90 (90 ± 3%) and negative for CD45 (1.2 ± 0.1%), thereby expressing the mesenchymal cell specific markers reported by our group and others [6, 29]
We performed a 3D coculture system of ASCs with endothelial cells to further demonstrate the capacity of ASCs to migrate, contact and localize around the endothelial cells, providing support and stability to the developed capillary-like structures (Fig. 1a, b)
Summary
Myocardial microvascular loss after myocardial infarction (MI) remains a therapeutic challenge. The presence of cardiovascular risk factors and metabolic disorders in cardiac patients seems to negatively influence the effects of adult stem/progenitor stem cells, discouraging their autologous use in the clinical setting [5]. In this regard, allogenic adipose-derived stem cells (ASCs) from obese patients display an impaired angiogenic potential [6, 7] and clustering of risk factors has been shown to reduce ASC and bone-marrow-derived cell pluripotency and self-renewal [8,9,10,11]. The use of allogenic stem cells from healthy donors may overcome these limitations
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