Prostaglandin E1 Reduces Apoptosis and Improves the Homing of Mesenchymal Stem Cells in Pulmonary Arterial Hypertension by Regulating Hypoxia-inducible Factor 1 Alpha

Overview

Journal Stem Cell Res Ther

Publisher Biomed Central

Date 2022 Jul 16

PMID 35842683

Authors

De-Tian Jiang

Lei Tuo

Xiao Bai

Wei-Dong Bing

Qing-Xi Qu

Xin Zhao

Guang-Min Song

Yan-Wen Bi

Wen-Yu Sun

Affiliations

Soon will be listed here.

Abstract

Background: Pulmonary arterial hypertension (PAH) is associated with oxidative stress and affects the survival and homing of transplanted mesenchymal stem cells (MSCs) as well as cytokine secretion by the MSCs, thereby altering their therapeutic potential. In this study, we preconditioned the MSCs with prostaglandin E1 (PGE1) and performed in vitro and in vivo cell experiments to evaluate the therapeutic effects of MSCs in rats with PAH.

Methods: We studied the relationship between PGE1 and vascular endothelial growth factor (VEGF) secretion, B-cell lymphoma 2 (Bcl-2) expression, and C-X-C chemokine receptor 4 (CXCR4) expression in MSCs and MSC apoptosis as well as migration through the hypoxia-inducible factor (HIF) pathway in vitro. The experimental rats were randomly divided into five groups: (I) control group, (II) monocrotaline (MCT) group, (III) MCT + non-preconditioned (Non-PC) MSC group, (IV) MCT + PGE1-preconditioned (PGE1-PC) MSC group, and (V) MCTMSC group. We studied methane dicarboxylic aldehyde (MDA) levels, MSC homing to rat lungs, mean pulmonary artery pressure, pulmonary artery systolic pressure, right ventricular hypertrophy index, wall thickness index (%WT), and relative wall area index (%WA) of rat pulmonary arterioles.

Results: Preconditioning with PGE1 increased the protein levels of HIF-1 alpha (HIF-1α) in MSCs, which can reduce MSC apoptosis and increase the protein levels of CXCR4, MSC migration, and vascular endothelial growth factor secretion. Upon injection with MSCs, the pulmonary artery systolic pressure, mean pulmonary artery pressure, right ventricular hypertrophy index, %WT, and %WA decreased in rats with PAH. MSCs exhibited better therapeutic effects than MSCs. Interestingly, lificiguat (YC-1), an inhibitor of the HIF pathway, blocked the effects of PGE1 preconditioning.

Conclusions: Our findings indicate that PGE1 modulates the properties of MSCs by regulating the HIF pathway, providing insights into the mechanism by which PGE1 preconditioning can be used to improve the therapeutic potential of MSCs in PAH.

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References

Meng S, Xu X, Chang W, Lu Z, Huang L, Xu J . LincRNA-p21 promotes mesenchymal stem cell migration capacity and survival through hypoxic preconditioning. Stem Cell Res Ther. 2018; 9(1):280. PMC: 6202870. DOI: 10.1186/s13287-018-1031-x. View

Xiao Y, Chen P, Zhou R, Zhang Y, Tian Z, Zhang S . Pathological Mechanisms and Potential Therapeutic Targets of Pulmonary Arterial Hypertension: A Review. Aging Dis. 2020; 11(6):1623-1639. PMC: 7673851. DOI: 10.14336/AD.2020.0111. View

Lin C, Lan Y, Ou M, Ji L, Lin S . Expression of miR-217 and HIF-1α/VEGF pathway in patients with diabetic foot ulcer and its effect on angiogenesis of diabetic foot ulcer rats. J Endocrinol Invest. 2019; 42(11):1307-1317. DOI: 10.1007/s40618-019-01053-2. View

Wu K, Zhou K, Wang Y, Zhou Y, Tian N, Wu Y . Stabilization of HIF-1α by FG-4592 promotes functional recovery and neural protection in experimental spinal cord injury. Brain Res. 2015; 1632:19-26. DOI: 10.1016/j.brainres.2015.12.017. View

Bai X, Xi J, Bi Y, Zhao X, Bing W, Meng X . TNF-α promotes survival and migration of MSCs under oxidative stress via NF-κB pathway to attenuate intimal hyperplasia in vein grafts. J Cell Mol Med. 2017; 21(9):2077-2091. PMC: 5571532. DOI: 10.1111/jcmm.13131. View

Smadja D, Levy M, Huang L, Rossi E, Blandinieres A, Israel-Biet D . Treprostinil indirectly regulates endothelial colony forming cell angiogenic properties by increasing VEGF-A produced by mesenchymal stem cells. Thromb Haemost. 2015; 114(4):735-47. PMC: 6570989. DOI: 10.1160/TH14-11-0907. View

Zhang P, Liu X, Li M, Ma Y, Sun H, Tian X . AT-533, a novel Hsp90 inhibitor, inhibits breast cancer growth and HIF-1α/VEGF/VEGFR-2-mediated angiogenesis in vitro and in vivo. Biochem Pharmacol. 2019; 172:113771. DOI: 10.1016/j.bcp.2019.113771. View

Zhang Q, Cheng X, Zhang H, Zhang T, Wang Z, Zhang W . Dissecting molecular mechanisms underlying HO-induced apoptosis of mouse bone marrow mesenchymal stem cell: role of Mst1 inhibition. Stem Cell Res Ther. 2020; 11(1):526. PMC: 7724846. DOI: 10.1186/s13287-020-02041-7. View

Loisel F, Provost B, Haddad F, Guihaire J, Amsallem M, Vrtovec B . Stem cell therapy targeting the right ventricle in pulmonary arterial hypertension: is it a potential avenue of therapy?. Pulm Circ. 2018; 8(2):2045893218755979. PMC: 5844533. DOI: 10.1177/2045893218755979. View

10.

Granton J, Langleben D, Kutryk M, Camack N, Galipeau J, Courtman D . Endothelial NO-Synthase Gene-Enhanced Progenitor Cell Therapy for Pulmonary Arterial Hypertension: The PHACeT Trial. Circ Res. 2015; 117(7):645-54. DOI: 10.1161/CIRCRESAHA.114.305951. View

11.

Benza R, Miller D, Barst R, Badesch D, Frost A, McGoon M . An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012; 142(2):448-456. DOI: 10.1378/chest.11-1460. View

12.

He G, Li L, Guan E, Chen J, Qin Y, Xie Y . Fentanyl inhibits the progression of human gastric carcinoma MGC-803 cells by modulating NF-κB-dependent gene expression . Oncol Lett. 2016; 12(1):563-571. PMC: 4907324. DOI: 10.3892/ol.2016.4619. View

13.

Speth J, Hoggatt J, Singh P, Pelus L . Pharmacologic increase in HIF1α enhances hematopoietic stem and progenitor homing and engraftment. Blood. 2013; 123(2):203-7. PMC: 3888286. DOI: 10.1182/blood-2013-07-516336. View

14.

Fukumitsu M, Suzuki K . Mesenchymal stem/stromal cell therapy for pulmonary arterial hypertension: Comprehensive review of preclinical studies. J Cardiol. 2019; 74(4):304-312. DOI: 10.1016/j.jjcc.2019.04.006. View

15.

Ejtehadifar M, Shamsasenjan K, Movassaghpour A, Akbarzadehlaleh P, Dehdilani N, Abbasi P . The Effect of Hypoxia on Mesenchymal Stem Cell Biology. Adv Pharm Bull. 2015; 5(2):141-9. PMC: 4517092. DOI: 10.15171/apb.2015.021. View

16.

Zeng K, Deng B, Jiang H, Wang M, Hua P, Zhang H . Prostaglandin E₁ protects bone marrow-derived mesenchymal stem cells against serum deprivation-induced apoptosis. Mol Med Rep. 2015; 12(4):5723-9. PMC: 4581785. DOI: 10.3892/mmr.2015.4176. View

17.

Akkinapally S, Hundalani S, Kulkarni M, Fernandes C, Cabrera A, Shivanna B . Prostaglandin E1 for maintaining ductal patency in neonates with ductal-dependent cardiac lesions. Cochrane Database Syst Rev. 2018; 2:CD011417. PMC: 6491149. DOI: 10.1002/14651858.CD011417.pub2. View

18.

Liu X, Kirschenbaum A, Lu M, Yao S, Dosoretz A, Holland J . Prostaglandin E2 induces hypoxia-inducible factor-1alpha stabilization and nuclear localization in a human prostate cancer cell line. J Biol Chem. 2002; 277(51):50081-6. DOI: 10.1074/jbc.M201095200. View

19.

Cruz F, Rocco P . The potential of mesenchymal stem cell therapy for chronic lung disease. Expert Rev Respir Med. 2019; 14(1):31-39. DOI: 10.1080/17476348.2020.1679628. View

20.

De Mendonca L, Felix N, Blanco N, da Silva J, Ferreira T, Abreu S . Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension. Stem Cell Res Ther. 2017; 8(1):220. PMC: 5627397. DOI: 10.1186/s13287-017-0669-0. View