Exosomes derived from human amniotic fluid mesenchymal stem cells alleviate cardiac fibrosis via enhancing angiogenesis in vivo and in vitro

Abstract

Background: Cardiac fibrosis is a pathological process characterized by excess extracellular matrix (ECM) deposition and plays a critical role in nearly all types of heart disease. The mechanism of cardiac fibrosis is still unclear and no effective medication treatment of cardiac fibrosis. Research showed that mesenchymal stem cell (MSC) derived exosomes may play a critical role in cardiac fibrosis. The effect of human amniotic fluid MSC (hAFMSC)-derived exosomes (hAFMSCExos) on cardiac fibrosis has remained unclear.Methods: The hAFMSCExos were extracted using a sequential centrifugation approach. The effects of hAFMSCExos on angiogenesis were analyzed both in human umbilical vein endothelial cells (HUVECs) after oxygen and glucose deprivation (OGD) in vitro, and in isoproterenol (ISO) induced-cardiac fibrosis in vivo.Results: The hAFMSCExos remarkably up-regulate the motility and migration of HUVECs after OGD compared with phosphate-buffered saline (PBS). Meanwhile, total tube length, total branching points and total loops were significantly raised in HUVECs after OGD treated with hAFMSCExos. The hAFMSCExos alleviated the cardiac fibrosis degree tested by hematoxylin-eosin (H&E) and Masson staining. The protein levels of Collagen I and α-smooth muscle actin (α-SMA) were lower in exosomes group rats than PBS group. Immunofluorescence suggested that hAFMSCExos can promote the expression of CD31 in the rats.Meanwhile, the number of regenerated microvessels was significantly enhanced in rats administrated with exosomes by quantitative analysis of microvessel density. Furthermore, the micro-CT scanning evidenced that hAFMSCExos promote angiogenesis after cardiac fibrosis. The levels of hypoxia-inducible factor 1 α (HIF-1α) and vascular endothelial growth factor (VEGF) expression in the left ventricle accepted HUVECs were higher than PBS treatment at 7 days post-treatment by Western blot analysis. Conclusions:The hAFMSCExos have proangiogenic effects on endothelial cells and enhanced angiogenesis in cardiac fibrosis. The hAFMSCExos may be a promising potential treatment strategy for cardiac fibrosis.

The Role of MSC in Wound Healing, Scarring and Regeneration

“…It has been proposed that MSC-derived exosomes are effective for reducing myocardial ischemia and reperfusion damage [ 135 , 138 ]. Hu et al described the proangiogenic effects on endothelial cells in vitro, stating that exosomes derived from human amniotic fluid MSCs alleviate cardiac fibrosis via enhancing angiogenesis [ 139 ].…”

Stem cells for treatment of liver fibrosis/cirrhosis: clinical progress and therapeutic potential

“…Condition medium derived from MSC treatment caused upregulation of the proangiogenic factors VEGF-A, angiotensin-1 (Ang-1), and receptors VEGF-R1 (Fms-like tyrosine kinase 1; Flt1) and VEGF-R2 (Fetal-like kinase 1; Flk1) [ 99 ]. Meanwhile, the number of regenerated microvessels was enhanced by administrating with MSC-derived exosomes [ 100 ]. Activation of VEGF-A signaling promoted liver cell proliferation through an increased blood supply and the release of paracrine factors.…”

Small Extracellular Vesicles from Human Amniotic Fluid Samples as Promising Theranostics

“…Notably, while effective in vivo, such EV formulation did not exert relevant pro-survival effects on isolated primary cardiomyocytes in vitro, suggesting that their cardioprotective potential could be exerted via an indirect mechanism of action; similar to hAFSC-EVs, these hAF-MSC-EVs were not proangiogenic on cardiovascular cells, yet they stimulated endothelial progenitor migration [ 19 ]. In a rat model of isoproterenol (ISO)-induced cardiac fibrosis, small hAF-MSC-EV treatment concurred to decrease the expression of pro-fibrotic markers, while increasing micro-vessel density within the myocardium [ 82 ]. hAFSC have also been described to be effective in counteracting and delaying the progression of fibrosis in the kidneys of preclinical animal models of Alport Syndrome; thus, hAFSC-EVs were tested to assess whether they could be responsible for such renoprotection.…”