StemRegenin-1 Attenuates Endothelial Progenitor Cell Senescence by Regulating the AhR Pathway-Mediated CYP1A1 and ROS Generation

Hye Ji Lim; Woong Bi Jang; Vinoth Kumar Rethineswaran; Jaewoo Choi; Eun Ji Lee; Sangmi Park; Yeoreum Jeong; Jong Seong Ha; Jisoo Yun; Young Jin Choi; Young Joon Hong; Sang-Mo Kwon

doi:10.3390/cells12152005

StemRegenin-1 Attenuates Endothelial Progenitor Cell Senescence by Regulating the AhR Pathway-Mediated CYP1A1 and ROS Generation

Cells. 2023 Aug 5;12(15):2005. doi: 10.3390/cells12152005.

Authors

Hye Ji Lim^{1

2}, Woong Bi Jang^{1

2}, Vinoth Kumar Rethineswaran^{1

2}, Jaewoo Choi^{1

2}, Eun Ji Lee^{1

2}, Sangmi Park^{1

2}, Yeoreum Jeong^{1

2}, Jong Seong Ha^{1

2}, Jisoo Yun^{1

2}, Young Jin Choi³, Young Joon Hong⁴, Sang-Mo Kwon^{1

2}

Affiliations

¹ Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.
² Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea.
³ Department of Hemato-Oncology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.
⁴ Department of Cardiology, Chonnam National University School of Medicine, Chonnam National University Hospital, Gwangju 61469, Republic of Korea.

Abstract

Endothelial progenitor cell (EPC)-based stem cell therapy is a promising therapeutic strategy for vascular diseases. However, continuous in vitro expansion for clinical studies induces the loss of EPC functionality due to aging. In this study, we investigated the effects of StemRegenin-1 (SR-1), an antagonist of aryl hydrocarbon receptor (AhR), on replicative senescence in EPCs. We found that SR-1 maintained the expression of EPC surface markers, including stem cell markers, such as CD34, c-Kit, and CXCR4. Moreover, SR-1 long-term-treated EPCs preserved their characteristics. Subsequently, we demonstrated that SR-1 showed that aging phenotypes were reduced through senescence-associated phenotypes, such as β-galactosidase activity, SMP30, p21, p53, and senescence-associated secretory phenotype (SASP). SR-1 treatment also increased the proliferation, migration, and tube-forming capacity of senescent EPCs. SR-1 inhibited the AhR-mediated cytochrome P450 (CYP)1A1 expression, reactive-oxygen species (ROS) production, and DNA damage under oxidative stress conditions in EPCs. Furthermore, as a result of CYP1A1-induced ROS inhibition, it was found that accumulated intracellular ROS were decreased in senescent EPCs. Finally, an in vivo Matrigel plug assay demonstrated drastically enhanced blood vessel formation via SR-1-treated EPCs. In summary, our results suggest that SR-1 contributes to the protection of EPCs against cellular senescence.

Keywords: AhR pathway; StemRegenin-1; human endothelial progenitor cells; reactive oxygen species; replicative senescence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cytochrome P-450 CYP1A1 / metabolism
Endothelial Progenitor Cells* / metabolism
Reactive Oxygen Species / metabolism
Receptors, Aryl Hydrocarbon / metabolism

Substances

Reactive Oxygen Species
Receptors, Aryl Hydrocarbon
Cytochrome P-450 CYP1A1

Grants and funding

This work was supported by a grant from the National Research Foundation (NRF2020R1A2C2101297, 2020R1I1A3074806, 2020R1I1A1A01072296 and 2022R1A5A2027161), funded by the Korean Government. This research was supported by the Korean Fund for Regenerative Medicine (KFRM) gran, funded by the Korea Government (the Ministry of Science and ICT, the Ministry of Health and Welfare) (21A0101L1).