Combined hypoxia inducible factor-1α and homogeneous endothelial progenitor cell therapy attenuates shunt flow–induced pulmonary arterial hypertension in rabbits

Cao, Guangqing; Liu, Chuanzhen; Wan, Zhaojie; Li, Kai; Sun, Honggang; Sun, Xiangfei; Tang, Mengmeng; Bing, Weidong; Wu, Shanshan; Pang, Xinyan; Zhang, Xiquan

doi:10.1016/j.jtcvs.2015.05.035

Cited by 19 publications

(10 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since HO activity appears to be necessary for EPC-mediated repair, this suggests that EPC therapy for PAH patients could be coupled to HO-1 induction using, e.g., EPO. This is further supported by recent evidence that EPC therapy is more efficient when HIF-1alpha, an inductor of HO-1-expression, is activated ( 50 ).…”

Section: Discussionsupporting

confidence: 55%

Erythropoietin Attenuates Pulmonary Vascular Remodeling in Experimental Pulmonary Arterial Hypertension through Interplay between Endothelial Progenitor Cells and Heme Oxygenase

et al. 2015

View full text Add to dashboard Cite

BackgroundPulmonary arterial hypertension (PAH) is a pulmonary vascular disease with a high mortality, characterized by typical angio-proliferative lesions. Erythropoietin (EPO) attenuates pulmonary vascular remodeling in PAH. We postulated that EPO acts through mobilization of endothelial progenitor cells (EPCs) and activation of the cytoprotective enzyme heme oxygenase-1 (HO-1).MethodsRats with flow-associated PAH, resembling pediatric PAH, were treated with HO-1 inducer EPO in the presence or absence of the selective HO-activity inhibitor tin-mesoporphyrin (SnMP). HO activity, circulating EPCs and pulmonary vascular lesions were assessed after 3 weeks.ResultsIn PAH rats, circulating EPCs were decreased and HO activity was increased compared to control. EPO treatment restored circulating EPCs and improved pulmonary vascular remodeling, as shown by a reduced wall thickness and occlusion rate of the intra-acinar vessels. Inhibition of HO activity with SnMP aggravated PAH. Moreover, SnMP treatment abrogated EPO-induced amelioration of pulmonary vascular remodeling, while surprisingly further increasing circulating EPCs as compared with EPO alone.ConclusionIn experimental PAH, EPO treatment restored the number of circulating EPCs to control level, improved pulmonary vascular remodeling, and showed important interplay with HO activity. Inhibition of increased HO activity in PAH rats exacerbated progression of pulmonary vascular remodeling, despite the presence of restored number of circulating EPCs. We suggest that both EPO-induced HO-1 and EPCs are promising targets to ameliorate the pulmonary vasculature in PAH.

show abstract

Section: Discussionsupporting

confidence: 55%

Erythropoietin Attenuates Pulmonary Vascular Remodeling in Experimental Pulmonary Arterial Hypertension through Interplay between Endothelial Progenitor Cells and Heme Oxygenase

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Cell-based gene therapy has been found to be effective in preclinical models of PAH ( 5 , 6 ). Several studies have indicated that prepro calcitonin gene-related peptide (CGRP)-transfected EPCs, vascular endothelial growth factor-transfected EPCs, and hypoxia inducible factor 1α-transfected EPCs could effectively attenuate PAH and reverse pulmonary vascular remodeling ( 7 – 9 ). A PHACeT clinical trial reported that short-term hemodynamic improvement and the associated long-term benefits in functional and quality of life were evidenced in patients with PAH by delivering endothelial NO-synthase (eNOS) gene-enhanced EPCs ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Combination treatment of adipose-derived stem cells and adiponectin attenuates pulmonary arterial hypertension in rats by inhibiting pulmonary arterial smooth muscle cell proliferation and regulating the AMPK/BMP/Smad pathway

Zheng

Lian

et al. 2017

Int J Mol Med

View full text Add to dashboard Cite

The present study aimed to assess the effects of therapy with adiponectin (APN) gene-modified adipose-derived stem cells (ADSCs) on pulmonary arterial hypertension (PAH) in rats and the underlying cellular and molecular mechanisms. ADSCs were successfully isolated from the rats and characterized. ADSCs were effectively infected with the green fluorescent protein (GFP)-empty (ADSCs-V) or the APN-GFP (ADSCs-APN) lentivirus and the APN expression was evaluated by ELISA. Sprague-Dawley rats were administered monocrotaline (MCT) to develop PAH. The rats were treated with MCT, ADSCs, ADSCs-V and ADSCs-APN. Then ADSCs-APN in the lung were investigated by confocal laser scanning microscopy and western blot analysis. Engrafted ADSCs in the lung were located around the vessels. Mean pulmonary arterial pressure (mPAP) and the right ventricular hypertrophy index (RVHI) in the ADSCs-APN-treated mice were significantly decreased as compared with the ADSCs and ADSCs-V treatments. Pulmonary vascular remodeling was assessed. Right ventricular (RV) function was evaluated by echocardiography. We found that pulmonary vascular remodeling and the parameters of RV function were extensively improved after ADSCs-APN treatment when compared with ADSCs and ADSCs-V treatment. Pulmonary artery smooth muscle cells (PASMCs) were isolated from the PAH rats. The antiproliferative effect of APN on PASMCs was assayed by Cell Counting Kit-8. The influence of APN and specific inhibitors on the levels of bone morphogenetic protein (BMP), adenosine monophosphate activated protein kinase (AMPK), and small mothers against decapentaplegia (Smad) pathways was detected by western blot analysis. We found that APN suppressed the proliferation of PASMCs isolated from the PAH rats by regulating the AMPK/BMP/Smad pathway. This effect was weakened by addition of the AMPK inhibitor (compound C) and BMP2 inhibitor (noggin). Therefore, combination treatment with ADSCs and APN effectively attenuated PAH in rats by inhibiting PASMC proliferation and regulating the AMPK/BMP/Smad pathway.

show abstract

“…Hypoxic–ischemic injury in stroke and myocardial infarction is well known with many stem cell treatments. Nowadays, combinations with different gene manipulations or drug preconditions in stem/progenitor cells are mostly used to study the therapeutic effect on in-vivo ischemic injury [ 40 – 42 ]. However, the concern of gene manipulation and its safety for transplanting cells are always raised in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Endothelial differentiation of bone marrow mesenchyme stem cells applicable to hypoxia and increased migration through Akt and NFκB signals

Liu

Tsai

et al. 2017

Stem Cell Res Ther

View full text Add to dashboard Cite

BackgroundBone marrow mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) are used to repair hypoxic or ischemic tissue. However, the underlining mechanism of resistance in the hypoxic microenvironment and the efficacy of migration to the injured tissue are still unknown. The current study aims to understand the hypoxia resistance and migration ability of MSCs during differentiation toward endothelial lineages by biochemical and mechanical stimuli.MethodMSCs were harvested from the bone marrow of 6–8-week-old Sprague–Dawley rats. The endothelial growth medium (EGM) was added to MSCs for 3 days to initiate endothelial differentiation. Laminar shear stress was used as the fluid mechanical stimulation.ResultsApplication of EGM facilitated the early endothelial lineage cells (eELCs) to express EPC markers. When treating the hypoxic mimetic desferrioxamine, both MSCs and eELCs showed resistance to hypoxia as compared with the occurrence of apoptosis in rat fibroblasts. The eELCs under hypoxia increased the wound closure and C-X-C chemokine receptor type 4 (CXCR4) gene expression. Although the shear stress promoted eELC maturation and aligned cells parallel to the flow direction, their migration ability was not superior to that of eELCs either under normoxia or hypoxia. The eELCs showed higher protein expressions of CXCR4, phosphorylated Akt (pAkt), and endogenous NFκB and IκBα than MSCs under both normoxia and hypoxia conditions. The potential migratory signals were discovered by inhibiting either Akt or NFκB using specific inhibitors and revealed decreases of wound closure and transmigration ability in eELCs.ConclusionThe Akt and NFκB pathways are important to regulate the early endothelial differentiation and its migratory ability under a hypoxic microenvironment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0470-0) contains supplementary material, which is available to authorized users.

show abstract

Combined hypoxia inducible factor-1α and homogeneous endothelial progenitor cell therapy attenuates shunt flow–induced pulmonary arterial hypertension in rabbits

Abstract: Both the therapy with HIF-1α-transfected EPCs, and EPC transplantation, attenuated shunt flow-induced PAH, by means of an angiogenic effect. The former therapeutic method was more effective.

Cited by 19 publications

References 43 publications

Erythropoietin Attenuates Pulmonary Vascular Remodeling in Experimental Pulmonary Arterial Hypertension through Interplay between Endothelial Progenitor Cells and Heme Oxygenase

Erythropoietin Attenuates Pulmonary Vascular Remodeling in Experimental Pulmonary Arterial Hypertension through Interplay between Endothelial Progenitor Cells and Heme Oxygenase

Combination treatment of adipose-derived stem cells and adiponectin attenuates pulmonary arterial hypertension in rats by inhibiting pulmonary arterial smooth muscle cell proliferation and regulating the AMPK/BMP/Smad pathway

Endothelial differentiation of bone marrow mesenchyme stem cells applicable to hypoxia and increased migration through Akt and NFκB signals

Contact Info

Product

Resources

About