Heme oxygenase-1 gene modified human placental mesenchymal stem cells promote placental angiogenesis and spiral artery remodeling by improving the balance of angiogenic factors in vitro

Abstract

Introduction: Abnormal placental vascular development is a possible cause of preeclampsia. Mesenchymal stem cell (MSC)-based therapy is a promising approach for tissue repair and angiogenesis. Further, heme oxygenase-1 (HO-1) has beneficial effects on the angiogenic balance during pregnancy. We explored the effects of HO-1 overexpression on placental vascularization using human placenta-derived MSCs (hPMSCs).

Methods: hPMSCs were isolated from term placenta, and the HO-1 gene was transfected with a lentivirus. Proliferation, migration, and apoptosis of hPMSCs and HO-hPMSCs were examined using CCK8 assay, trans-well assay, and flow cytometry, respectively. Paracrine secretion of the angiogenesis factors VEGF and PlGF, as well as the anti-angiogenesis factors sFlt-1 and sEng, from hPMSC/HO-hPMSCs was measured by qRT-PCR and ELISA. Human umbilical cord endothelial cells and a villus-decidua co-culture were treated with conditioned media to study the effect of HO-1-hPMSCs on tube formation and villus vascular remodeling.

Results: HO-1 significantly improved the proliferation and migration of hPMSCs. Additionally, HO-1 reduced hPMSCs apoptosis. The levels of VEGF were increased in HO-1-hPMSCs, whereas those of sFlt-1 decreased. Tube formation assays showed that the conditioned media from HO-1-hPMSCs resulted in more branching points than those from the controls. The villus-decidua co-culture system confirmed that HO-1-hPMSCs are conducive to angiogenesis and vascular remodeling.

Discussion: HO-1-modified hPMSCs improve placental vascularization by promoting a balance of pro- and anti- angiogenesis factors, which is worthy of further study as an alternative treatment for preeclampsia.

Keywords: HO-1; Placenta-derived mesenchymal stem cells; Placental angiogenesis; Preeclampsia; Spiral artery remodeling.