Peptide hormone ELABELA promotes rat bone marrow-derived mesenchymal stem cell proliferation and migration by manipulating the cell cycle through the PI3K/AKT pathway under the hypoxia and ischemia microenvironment

Stem Cell Research & Therapy - Tập 13 Số 1 - 2022
Xuxiang Chen1, Changqing Zhou1, Daishi Xu1, Xin Liu1, Shuangmei Li1, Jingyu Hou1, Kanglong Zhang2, Chaotao Zeng2, Guanghui Zheng2, Haidong Wu1, Hao Wu2, Wuming Wang1, Jiaying Fu1, Tong Wang1
1Department of Emergency, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, Guangdong, People's Republic of China
2Department of Emergency, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, Guangdong, People’s Republic of China

Tóm tắt

AbstractBackgroundMesenchymal stem cells (MSCs) are emerging as a potential candidate for stem cell transplantation to repair myocardial tissue in myocardial infarctions (MI). However, there are some pivotal limitations such as poor survival and low migration capacity of MSCs in hypoxic and ischemic microenvironments of MI. Our previous work verified that ELABELA (also abbreviated as ELA), a peptide hormone, could play a role as a growth factor and prolong the life span of rat bone marrow-derived mesenchymal stem cells (RAT BM-MSCs) under hypoxic and ischemic conditions. Nevertheless, the influence of ELA on the cell cycle, proliferation, and migration remains elusive. This study will further explore the improvement of the biological functions of ELA-treated RAT BM-MSCs, so as to provide a reference for improving the efficacy of RAT BM-MSCs in MI.MethodsRat BM-MSCs were isolated from 80 to 120 g Sprague Dawley rats by flushing femurs and tibias under the aseptic condition. RAT BM-MSCs of the third passage were divided into control group, hypoxic/ischemic (H/I) group, ELA group, ELA-LY group and LY group. RAT BM-MSCs were cultured under normoxia in control group. In H/I group, RAT BM-MSCs were exposed to hypoxia (1% O2) and serum deprivation for 24 h. RAT BM-MSCs in ELA group were treated with 5 µM ELA prior to the H/I exposure for 24 h. The PI3K/AKT inhibitor, LY294002 (50 µM), was used in ELA-LY group and LY group to observe the effect of ELA on PI3K/AKT activation. Cell proliferation ability was examined by CCK-8. Cell cycle was assessed with flow cytometry. Cell migration was evaluated by Transwell assay. Expression levels of total-AKT, phosphorylated-AKT, and cell cycle-associated proteins were examined by Western blotting.ResultsELA-treated RAT BM-MSCs exhibited significantly higher proliferation ability, cell viability, and migration under H/I conditions. The cell cycle analysis showed that an increased proportion of cells in the S and G2/M phases of the cell cycle were observed in ELA-treated RAT BM-MSCs. The addition of ELA activated the PI3K/AKT signaling pathway. Additionally, upon treating with the inhibitor of the PI3K/AKT signaling pathway, ELA-triggered proliferation, cell viability, and migration were abrogated.ConclusionsELA can be used to enhance the proliferation ability, cell viability, and migration of RAT BM-MSCs through the PI3K/AKT signaling pathway and alleviate cell cycle arrest at the G0/G1 phase under hypoxic and ischemic injury. Thus, this study provides a promising strategy that ELA may help to optimize the mesenchymal stem cell-based therapy in MI.

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Tài liệu tham khảo

Ye X, Zhang C. Effects of hyperlipidemia and cardiovascular diseases on proliferation, differentiation and homing of mesenchymal stem cells. Curr Stem Cell Res Ther. 2017;12(5):377–87.

Miao C, Lei M, Hu W, Han S, Wang Q. A brief review: the therapeutic potential of bone marrow mesenchymal stem cells in myocardial infarction. Stem Cell Res Ther. 2017;8(1):242.

White SJ, Chong JJH. Mesenchymal stem cells in cardiac repair: effects on myocytes, vasculature, and fibroblasts. Clin Ther. 2020;42(10):1880–91.

Abu-El-Rub E, Sareen N, Lester Sequiera G, Ammar HI, Yan W, ShamsEldeen AM, et al. Hypoxia-induced increase in Sug1 leads to poor post-transplantation survival of allogeneic mesenchymal stem cells. FASEB J. 2020;34(9):12860–76.

Clark AY, Martin KE, García JR, Johnson CT, Theriault HS, Han WM, et al. Integrin-specific hydrogels modulate transplanted human bone marrow-derived mesenchymal stem cell survival, engraftment, and reparative activities. Nat Commun. 2020;11(1):114.

Liu Z, Mikrani R, Zubair HM, Taleb A, Naveed M, Baig MMFA, et al. Systemic and local delivery of mesenchymal stem cells for heart renovation: challenges and innovations. Eur J Pharmacol. 2020;876:173049.

Saidova AA, Vorobjev IA. Lineage commitment, signaling pathways, and the cytoskeleton systems in mesenchymal stem cells. Tissue Eng Part B Rev. 2020;26(1):13–25.

Guo X, Bai Y, Zhang L, Zhang B, Zagidullin N, Carvalho K, et al. Cardiomyocyte differentiation of mesenchymal stem cells from bone marrow: new regulators and its implications. Stem Cell Res Ther. 2018;9(1):44.

Chng SC, Ho L, Tian J, Reversade B. ELABELA: a hormone essential for heart development signals via the apelin receptor. Dev Cell. 2013;27(6):672–80.

Ho L, Tan SY, Wee S, Wu Y, Tan SJ, Ramakrishna NB, et al. ELABELA is an endogenous growth factor that sustains hESC self-renewal via the PI3K/AKT pathway. Cell Stem Cell. 2015;17(4):435–47.

Ma Z, Song JJ, Martin S, Yang XC, Zhong JC. The Elabela-APJ axis: a promising therapeutic target for heart failure. Heart Fail Rev. 2020;26:1249–58.

Sato T, Sato C, Kadowaki A, Watanabe H, Ho L, Ishida J, et al. ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage. Cardiovasc Res. 2017;113(7):760–9.

Fu J, Chen X, Liu X, Xu D, Yang H, Zeng C, et al. ELABELA ameliorates hypoxic/ischemic-induced bone mesenchymal stem cell apoptosis via alleviation of mitochondrial dysfunction and activation of PI3K/AKT and ERK1/2 pathways. Stem Cell Res Ther. 2020;11(1):541.

Samakova A, Gazova A, Sabova N, Valaskova S, Jurikova M, Kyselovic J. The PI3k/Akt pathway is associated with angiogenesis, oxidative stress and survival of mesenchymal stem cells in pathophysiologic condition in ischemia. Physiol Res. 2019;68(Suppl 2):S131–8.

Popielarczyk TL, Huckle WR, Barrett JG. Human bone marrow-derived mesenchymal stem cells home via the PI3K-Akt, MAPK, and Jak/Stat signaling pathways in response to platelet-derived growth factor. Stem Cells Dev. 2019;28(17):1191–202.

Xie S, Jiang X, Wang R, Xie S, Hua Y, Zhou S, et al. Low-intensity pulsed ultrasound promotes the proliferation of human bone mesenchymal stem cells by activating PI3K/AKt signaling pathways. J Cell Biochem. 2019;120(9):15823–33.

Lu L, Chen G, Yang J, Ma Z, Yang Y, Hu Y, et al. Bone marrow mesenchymal stem cells suppress growth and promote the apoptosis of glioma U251 cells through downregulation of the PI3K/AKT signaling pathway. Biomed Pharmacother. 2019;112:108625.

Lee JH, Yun CW, Hur J, Lee SH. Fucoidan rescues p-cresol-induced cellular senescence in mesenchymal stem cells via FAK-Akt-TWIST axis. Mar Drugs. 2018;16(4):121.

Ryu JM, Lee MY, Yun SP, Han HJ. High glucose regulates cyclin D1/E of human mesenchymal stem cells through TGF-beta1 expression via Ca2+/PKC/MAPKs and PI3K/Akt/mTOR signal pathways. J Cell Physiol. 2010;224(1):59–70.

Hou J, Wang L, Wu Q, Zheng G, Long H, Wu H, et al. Long noncoding RNA H19 upregulates vascular endothelial growth factor A to enhance mesenchymal stem cells survival and angiogenic capacity by inhibiting miR-199a-5p. Stem Cell Res Ther. 2018;9(1):109.

Kobolak J, Dinnyes A, Memic A, Khademhosseini A, Mobasheri A. Mesenchymal stem cells: identification, phenotypic characterization, biological properties and potential for regenerative medicine through biomaterial micro-engineering of their niche. Methods. 2016;99:62–8.

He Q, Ye Z, Zhou Y, Tan WS. Comparative study of mesenchymal stem cells from rat bone marrow and adipose tissue. Turk J Biol. 2018;42:477–89.

Lalu MM, Mazzarello S, Zlepnig J, Dong YYR, Montroy J, McIntyre L, et al. Safety and efficacy of adult stem cell therapy for acute myocardial infarction and ischemic heart failure (SafeCell Heart): a systematic review and meta-analysis. Stem Cells Transl Med. 2018;7(12):857–66.

Rudman J, Frishman WH. Stem cell therapy for acute myocardial infarctions: a systematic review. Cardiol Rev. 2020;28(3):140–7.

Oggu GS, Sasikumar S, Reddy N, Ella KKR, Rao CM, Bokara KK. Gene delivery approaches for mesenchymal stem cell therapy: strategies to increase efficiency and specificity. Stem Cell Rev Rep. 2017;13(6):725–40.

Ranganath SH, Levy O, Inamdar MS, Karp JM. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell. 2012;10(3):244–58.

Jakovljevic J, Harrell CR, Fellabaum C, Arsenijevic A, Jovicic N, Volarevic V. Modulation of autophagy as new approach in mesenchymal stem cell-based therapy. Biomed Pharmacother. 2018;104:404–10.

Shen H, Cui G, Li Y, Ye W, Sun Y, Zhang Z, et al. Follistatin-like 1 protects mesenchymal stem cells from hypoxic damage and enhances their therapeutic efficacy in a mouse myocardial infarction model. Stem Cell Res Ther. 2019;10(1):17.

Liu W, Yan J, Pan W, Tang M. Apelin/Elabela-APJ: a novel therapeutic target in the cardiovascular system. Ann Transl Med. 2020;8(5):243.

Yu P, Ma S, Dai X, Cao F. Elabela alleviates myocardial ischemia reperfusion-induced apoptosis, fibrosis and mitochondrial dysfunction through PI3K/AKT signaling. Am J Transl Res. 2020;12(8):4467–77.

Norris ML, Pauli A, Gagnon JA, Lord ND, Rogers KW, Mosimann C, et al. Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling. Elife. 2017;6:e22626.

Xu J, Chen L, Jiang Z, Li L. Biological functions of Elabela, a novel endogenous ligand of APJ receptor. J Cell Physiol. 2018;233(9):6472–82.

Sharma B, Ho L, Ford GH, Chen HI, Goldstone AB, Woo YJ, et al. Alternative progenitor cells compensate to rebuild the coronary vasculature in Elabela- and Apj-deficient hearts. Dev Cell. 2017;42(6):655-666.e3.

Pack LR, Daigh LH, Meyer T. Putting the brakes on the cell cycle: mechanisms of cellular growth arrest. Curr Opin Cell Biol. 2019;60:106–13.

Li Y, Guo S, Liu W, Jin T, Li X, He X, et al. Silencing of SNHG12 enhanced the effectiveness of MSCs in alleviating ischemia/reperfusion injuries via the PI3K/AKT/mTOR signaling pathway. Front Neurosci. 2019;13:645.

Ye C, Zhang W, Hang K, Chen M, Hou W, Chen J, et al. Extracellular IL-37 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells via activation of the PI3K/AKT signaling pathway. Cell Death Dis. 2019;10(10):753.

Wang X, Liang G, Guo Q, Cai W, Zhang X, Ni J, et al. ELABELA improves endothelial cell function via the ELA-APJ axis by activating the PI3K/Akt signalling pathway in HUVECs and EA.hy926 cells. Clin Exp Pharmacol Physiol. 2020;47(12):1953–64.

Ma J, Hu H, Lin M, Chen L, Liu M, Li H, et al. ELABELA alleviates syncytiotrophoblast hypoxia/reoxygenation injury and preeclampsia-like symptoms in mice by reducing apoptosis. Placenta. 2021;106:30–9.

Ren S, Chen J, Duscher D, Liu Y, Guo G, Kang Y, et al. Microvesicles from human adipose stem cells promote wound healing by optimizing cellular functions via AKT and ERK signaling pathways. Stem Cell Res Ther. 2019;10(1):47.

Adamo A, Brandi J, Caligola S, Delfino P, Bazzoni R, Carusone R, et al. Extracellular vesicles mediate mesenchymal stromal cell-dependent regulation of B cell PI3K-AKT signaling pathway and actin cytoskeleton. Front Immunol. 2019;10:446.

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Stem Cell Research & Therapy

Tập 13 Số 1

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