HIF-1α overexpression in mesenchymal stem cell-derived exosomes mediates cardioprotection in myocardial infarction by enhanced angiogenesis

Abstract

Background: Myocardial infarction (MI) is a severe disease that often associated with dysfunction of angiogenesis. Cell-based therapies for MI using mesenchymal stem cell (MSC)-derived exosomes have been well studied due to their strong proangiogenic effect. Genetic modification is one of the most common methods to enhance exosome therapy. This study investigated the proangiogenic and cardioprotective effect of exosomes derived from hypoxiainducible factor 1-alpha (HIF-1α)-modified MSCs. Methods: Lentivirus containing HIF-1α overexpressing vector was packaged and used to infect MSCs. Exosomes were isolated from MSC-conditioned medium by ultracentrifugation. Human umbilical vein endothelial cells (HUVECs) were treated under hypoxia condition for 48 h co-cultured with PBS, control exosomes, or HIF-1αoverexpressed exosomes, respectively. Then the preconditioned HUVECs were subjected to tube formation assay, Transwell assay, and EdU assay to evaluate the protective effect of exosomes. Meanwhile, mRNA and secretion levels of proangiogenic factors were measured by RT-qPCR and ELISA assays. In vivo assays were conducted using the rat myocardial infarction model. PBS, control exosomes, or HIF-1α-overexpressed exosomes were injected through tail vein after MI surgery. Heart function was assessed by echocardiography at days 3, 14, and 28. At day 7, mRNA and protein expression levels of proangiogenic factors in the peri-infarction area and circulation were evaluated, respectively. At day 28, hearts were collected and subjected to H&E staining, Masson's trichrome staining, and immunofluorescent staining. Results: HIF-1α-overexpressed exosomes rescued the impaired angiogenic ability, migratory function, and proliferation of hypoxia-injured HUVECs. Simultaneously, HIF-1α-overexpressed exosomes preserved heart function by promoting neovessel formation and inhibiting fibrosis in the rat MI model. In addition, both in vitro and in vivo proangiogenic factors mRNA and protein expression levels were elevated after HIF-1α-overexpressed exosome application.

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

“…Current studies reported that HIF-1α directly regulates the expression of genes involved in angiogenesis (42,(50)(51)(52), which including VEGF, platelet-derived growth factor (PDGF), and angiopoietin 1 (Ang-1) (53). The research demonstrated HIF-1αoverexpressed exosomes had a cardioprotective effect on MI rat via enhanced angiogenesis and reduced fibrosis, there were promotional effects on proliferation, migration, and tube forming ability on HUVECs (54). Evidence has elucidated that HIF-1α regulated the expression of VEGF at the transcription level (55).…”

Exosomes derived from adipose-derived stem cells overexpressing Glyoxalase-1 protect endothelial cells and enhance angiogenesis in type 2 diabetic mice with limb ischemia

“…The speci c development approaches of the exosomes included surface engineering, genetic engineering, chemical modi cation, and membrane fusion [32][33][34]. Of which the genetic engineering generated overexpression of a speci c protein or micro-RNA and exhibited satisfactory outcome: Chen et al found that the GDNF-modi ed human ADSCs-derived exosomes ameliorated peritubular capillary loss in tubulointerstitial brosis [35]; Sun et al revealed that the exosomes derived from the HIF-1α overexpressed mesenchymal stem cells (MSCs) enhanced the angiogenesis to provide cardioprotection in myocardial infarction [36]; and Wang et al discovered that exosomes derived from miR-155-5poverexpressing synovial MSCs enhanced the bio functions of chondrocytes to prevent osteoarthritis [37].…”

3D bioprinting of integral ADSCs-NO hydrogel scaffolds to promote severe burn wound healing

“…HUVECs were cultured in DMEM supplemented with 10% FBS in a humidified atmosphere containing 5% CO 2 at 37°C. A total of 1 × 10 4 HUVECs were added to each Transwell (Corning, 3422) upper chamber, and 600 μl of fresh medium or culture supernatant containing 10% FBS was placed in the lower chamber [ 29 ]. HUVECs were treated with supernatant from 2D-ADSCs, 3D-ADSCs- or 3D-ADSCs/NO for 24 h, and the group without supernatant was the control group.…”