HAX1-Overexpression Augments Cardioprotective Efficacy of Stem Cell-Based Therapy Through Mediating Hippo-Yap Signaling-Reference-Cited by-同舟云学术

HAX1-Overexpression Augments Cardioprotective Efficacy of Stem Cell-Based Therapy Through Mediating Hippo-Yap Signaling

Published:2024-05-07 Issue:6 Volume:20 Page:1569-1586
ISSN:2629-3269
Container-title:Stem Cell Reviews and Reports
language:en
Short-container-title:Stem Cell Rev and Rep

Author:

Cai Wen-Feng,Jiang Lin,Liang Jialiang,Dutta Suchandrima,Huang Wei,He Xingyu,Wu Zhichao,Paul Christian,Gao Xiang,Xu Meifeng,Kanisicak Onur,Zheng Junmeng,Wang Yigang^ORCID

Abstract

AbstractAlthough stem/progenitor cell therapy shows potential for myocardial infarction repair, enhancing the therapeutic efficacy could be achieved through additional genetic modifications. HCLS1-associated protein X-1 (HAX1) has been identified as a versatile modulator responsible for cardio-protective signaling, while its role in regulating stem cell survival and functionality remains unknown. In this study, we investigated whether HAX1 can augment the protective potential of Sca1+ cardiac stromal cells (CSCs) for myocardial injury. The overexpression of HAX1 significantly increased cell proliferation and conferred enhanced resistance to hypoxia-induced cell death in CSCs. Mechanistically, HAX1 can interact with Mst1 (a prominent conductor of Hippo signal transduction) and inhibit its kinase activity for protein phosphorylation. This inhibition led to enhanced nuclear translocation of Yes-associated protein (YAP) and activation of downstream therapeutic-related genes. Notably, HAX1 overexpression significantly increased the pro-angiogenic potential of CSCs, as demonstrated by elevated expression of vascular endothelial growth factors. Importantly, implantation of HAX1-overexpressing CSCs promoted neovascularization, protected against functional deterioration, and ameliorated cardiac fibrosis in ischemic mouse hearts. In conclusion, HAX1 emerges as a valuable and efficient inducer for enhancing the effectiveness of cardiac stem or progenitor cell therapeutics. Graphical Abstract

Funder

National Heart, Lung, and Blood Institute

American Heart Association

Publisher

Springer Science and Business Media LLC

Link

https://link.springer.com/content/pdf/10.1007/s12015-024-10729-z.pdf

Reference59 articles.

1. Liu, X., Lei, J., Wang, K., Ma, L., Liu, D., Du, Y., Wu, Y., Zhang, S., Wang, W., Ma, X., Liu, H. (2017). Mitochondrial Omi/HtrA2 promotes caspase activation through cleavage of HAX-1 in aging heart. Rejuvenation Research, 20, 183–192. https://doi.org/10.1089/rej.2016.1861

2. Abdelwahid, E., Li, H., Wu, J., Irioda, A. C., de Carvalho, K. A., & Luo, X. (2016). Endoplasmic reticulum (ER) stress triggers Hax1-dependent mitochondrial apoptotic events in cardiac cells. Apoptosis, 21, 1227–1239. https://doi.org/10.1007/s10495-016-1286-6

3. Brodowska, K., Al-moujahed, A., Marmalidou, A., Meyer ZuHorste, M., Cichy, J., Miller, J. W., Gragoudas, E., & Vavvas, D. G. (2014). The clinically used photosensitizer Verteporfin (VP) inhibits YAP-TEAD and human retinoblastoma cell growth in vitro without light activation. Experimental Eye Research, 124, 67–73. https://doi.org/10.1016/j.exer.2014.04.011

4. Cai, W. F., Kang, K., Huang, W., Liang, J. L., Feng, Y. L., Liu, G. S., Chang, D. H., Wen, Z. L., Paul, C., Xu, M., Millard, R. W., & Wang, Y. (2015). CXCR4 attenuates cardiomyocytes mitochondrial dysfunction to resist ischaemia-reperfusion injury. Journal of Cellular and Molecular Medicine, 19, 1825–1835. https://doi.org/10.1111/jcmm.12554

5. Cai, W. F., Liu, G. S., Wang, L., Paul, C., Wen, Z. L., & Wang, Y. (2016). Repair Injured Heart by Regulating Cardiac Regenerative Signals. Stem Cells Int, 2016, 6193419. https://doi.org/10.1155/2016/6193419