Regulatory effects of EphB2 signaling on stem
cell aging and Nrf2-mediated antioxidative
mechanismCollege of Vet. Med. Veterinary PhysiologySeoul National University, South Korea
Young Hyun Jung
Advisor professor : Ho Jae Han, DVM, PhD
Dean, College of Vet. Medicine, Seoul National University

Presentation for Keiichiro Maeda Memorial Ise Award Lecture, 20210924

Introduction
Academic career
2007-2013 College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
2013-2021 College of Veterinary Medicine, Seoul National University, Seoul, Korea.
Research of interest
Identifying the molecular mechanism of stem cell aging and the antioxidative mechanism of extracellular bioactive molecules, such asnutrients, growth factors, hormone, and cytokines.

Hormone, Growth factors

Major achievements
Lee HJ*, Jung YH*, Choi GE, Kim JS, Chae CW, Lim JR, Kim SY, Yoon JH, Cho JH, Lee SJ, Han HJ. Urolithin A suppresses high glucoseinduced neuronal amyloidogenesis by modulating TGM2-dependent ER-mitochondria contacts and calcium homeostasis. Cell DeathDiffer. 2021 Jan;28(1):184-202. *Co-first author. IF : 15.828
Jung YH, Lee HJ, Kim JS, Lee SJ, Han HJ. EphB2 signaling-mediated Sirt3 expression reduces MSC senescence by maintaining
mitochondrial ROS homeostasis. Free Radic Biol Med. 2017 Sep;110:368-380. IF: 7.376
Jung YH, Lee SJ, Oh SY, Lee HJ, Ryu JM, Han HJ. Oleic acid enhances the motility of umbilical cord blood derived mesenchymal stem
cells through EphB2-dependent F-actin formation. Biochim Biophys Acta. 2015 Aug;1853(8):1905-17. IF: 4.739
Kim JS*, Jung YH*, Lee HJ, Chae CW, Choi GE, Lim JR, Kim SY, Lee JE, Han HJ. Melatonin activates ABCA1 via the BiP/NRF1 pathway
to suppress high-cholesterol-induced apoptosis of mesenchymal stem cells. Stem Cell Res Ther. 2021 Feb 5;12(1):114. *Co-firstauthor. IF: 6.832
Lee HJ*, Jung YH*, Choi GE, Kim JS, Chae CW, Lim JR, Kim SY, Lee JE, Park MC, Yoon JH, Choi MJ, Kim KS, Han HJ. O-cyclic
phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential ofmesenchymal stem cells. Cell Death Dis. 2019 Aug 5;10(8):590. *Co-first author. IF: 8.460

Mesenchymal stem cells and aging(Han et al., Cells, 2017)

Good but could be aged,
Can stem cells are reversed from aging?

(Oh et al., Nat Med, 2015)

MSCs and senescence

Proliferative but not infinite, Viable but not normal,
What to do?
(Zhou et al., Front. Cell Dev. Biol. 2020)

EphB2 expression in MSCs
Which EphBs expression in UCB-MSCs?

EphB2 expression is high in
intestinal stem cell niche(Proliferative and migratory)

Oleic acid induces Wnt/β-catenin signalingRelative mRNA expression level(fold of vehicle)

EphB2 expression in MSCs
4*3Vehicle
OA21*0EEph phEEEEErinB rpinh ph ph ph ph
2 B16 B4 B3 B2 B1

Oleic acid increased EphB2 expression

EphB2 expression is regulator of stem cell migration

EphB2 expression ↓à slow migration

EphB2 expression ↑à Filamentous actin ↑In vivo skin wound healing analysis

Injection of MSC around would sites

EphB2 expression↑
à Fast migration in skin wound sites

Differential expression levels of Ephrin/Ephs in MSCs
How about the change of EphBs expression in senescent MSCs?

Passage↑ àEphB2↓, EphrinB2↑

EphB2 activation
à Slow senescenceEffect of EphB2 signaling in anti-senescence of MSCs

EphB2 expression↓
à Stem cell senescence ↑Effect of EphB2 signaling in sirt3 expression

Stem cell senescenceà Sirt3 expression↓

EphB2 activation
à Mitochondrial Sirt3↑

Effect of EphB2 signaling in sirt3 expression

Sirt3 expression↓
à Stem cell senescenceMitochondrial dysfunctions and Nrf2

Nrf2, a master regulator of cellular redox homeostasis

Nrf2 regulation mechanism(Holmström et al., Curr Opin Toxicol. 2016)

Effect of EphB2 signaling in NRF-2 nuclear translocation

EphB2 à Nrf2 nuclear translocationEffect of EphB2 signaling in regulation of MnSOD

EphB2 activation
à MnSOD expression↑

EphB2 activation
à MnSOD activity↑Effect of Sirt3 expression on increasing MnSOD activity

EphB2 activation à mitochondrial ROS ↓Conclusion• OA enhances UCB-MSC motility through EphB2-dependent F-actin formation. (Jung et al.,BBA Mol Cell Res, 2015)• Priming EphB2 signaling could be a strategy for enhancing the replicative capacity of UCBMSCs in an in vitro culture and for increasing the therapeutic efficacy of UCB-MSCs inclinical use by preserving mtROS homeostasis. (Jung et al., FRBM, 2017)T h a n k y o u fo r y o u r a t t e n t io nPresentation for Keiichiro Maeda Memorial Ise Award, 2020 and 2021