Aims/hypothesis Autologous progenitor cells represent a promising option for regenerative cell-based therapies. Nevertheless, it has been shown that ageing and cardiovascular risk factors such as diabetes affect circulating endothelial and bone marrow-derived progenitor cells, limiting their therapeutic potential. However, their impact on other stem cell populations remains unclear. We therefore investigated the effects of diabetes on adipose-derived stem cells (ASCs) and whether these effects might limit the therapeutic potential of autologous ASCs. Methods A systems biology approach was used to analyse the expression of genes related to stem cell identification in subcutaneous adipose tissue (SAT), the stromal vascular fraction and isolated ASCs from Zucker diabetic fatty rats and their non-diabetic controls. An additional model of type 2 diabetes without obesity was also investigated. Bioinformatic approaches were used to investigate the biological significance of these changes. In addition, functional studies on cell viability and differentiation potential were performed. Results Widespread downregulation of mesenchymal stem cell markers was observed in SAT of diabetic rats. Gene expression and in silico analysis revealed a significant effect on molecules involved in the maintenance of pluripotency and self-renewal, and on the alteration of main signalling pathways important for stem cell maintenance. The viability and differentiation potential of ASCs from diabetic rats was impaired in in vitro models and in in vivo angiogenesis. Conclusions/interpretation The impact of type 2 diabetes on ASCs might compromise the efficiency of spontaneous selfrepair and direct autologous stem cell therapy.
We demonstrate that hypercholesterolemia induces HDL lipidomic changes, losing phosphatidylcholine-lipid species and gaining cholesteryl esters, and proteomic changes, with losses in cardioprotective proteins. These remodeling changes shifted HDL particles toward a dysfunctional state.
The precise mechanisms underlying the differential function and cardiometabolic risk of white adipose tissue (WAT) remain unclear. Visceral adipose tissue (V WAT ) and subcutaneous adipose tissue (SC WAT ) have different metabolic functions that seem to be ascribed to their different intrinsic expansion capacities. Here we have hypothesized that the WAT characteristics are determined by the resident adipose-derived stem cells (ASCs) found in the different WAT depots. Therefore, our objective has been to investigate adipogenesis in anatomically distinct fat depots. ASCs from five different WAT depots were characterized in both healthy lean and diabetic obese rats, showing significant differences in expression of some of genes governing the stemness and the earlier adipogenic differentiation steps. Notch-target genes [Hes (hairy and enhancer of split) and Hey (hairy/enhancer of split related with YRPW motif) families] were upregulated in ASCs derived from visceral depots. Upon adipogenic differentiation, adipocyte cell markers were downregulated in ASCs from V WAT in comparison to ASCs from SC WAT , revealing a lower adipogenic capacity in ASCs of visceral origin than in those of SC WAT in accordance with the differential activation of Notch signaling. Notch upregulation by its activator phenethyl isothiocyanate attenuated the adipogenic differentiation of ASCs from SC WAT whereas Notch inhibition by N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) increased the adipogenic differentiation of ASCs from visceral origin. In conclusion, the differential activation of Notch in ASCs is the origin of the different intrinsic WAT expansion capacities that contribute to the regional variations in WAT homeostasis and to its associated cardiometabolic risk.
LRP5 (low-density lipoprotein receptor-related protein 5) activates canonical Wnt signalling. LRP5 plays multiple roles including regulation of lipoprotein and cholesterol homeostasis as well as innate immunity cell function. However, it is not known whether LRP5 has a role in the myocardium. The aim of this study was to investigate LRP5 and Wnt signalling in myocardial remodelling after acute myocardial infarction (MI). Wnt protein levels were determined in a hypercholesterolemic porcine model of MI, in Lrp5 C57Bl6 mice, in cultured cardiomyocytes and in human explanted hearts with previous MI episodes. 21 days post-MI, there was upregulation of LRP5 in the ischemic myocardium of hypercholesterolemic pigs as well as an upregulated expression of proteins of the Wnt pathway. We demonstrate via overexpression and silencing experiments that LRP5 induces Wnt pathway activation in isolated cardiomyocytes. Hypoxia and lipid-loading induced the expression of Wnt proteins, whereas this effect is blocked in LRP5-silenced cardiomyocytes. To characterize the function of the LRP5-Wnt axis upregulation in the heart, we induced MI in wild-type and Lrp5 mice. Lrp5 mice had significantly larger infarcts than Wt mice, indicating a protective role of LRP5 in injured myocardium. The LRP5 upregulation in post-MI hearts seen in pigs and mice was also evident in human hearts as dyslipidemic patients with previous episodes of ischemia have higher expression of LRP5 and Wnt-signalling genes than non-ischemic dilated hearts. We demonstrate an upregulation of LRP5 and the Wnt signalling pathway that it is a prosurvival healing response of cardiomyocytes upon injury.
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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0509-2) contains supplementary material, which is available to authorized users.
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