2. Academic Validation
  3. Human cardiac stem cells rejuvenated by modulating autophagy with MHY-1685 enhance the therapeutic potential for cardiac repair

Human cardiac stem cells rejuvenated by modulating autophagy with MHY-1685 enhance the therapeutic potential for cardiac repair

  • Exp Mol Med. 2021 Sep;53(9):1423-1436. doi: 10.1038/s12276-021-00676-x.
Ji Hye Park  # 1 2,  Hyeok Kim  # 3,  Hyung Ryong Moon  # 4,  Bong-Woo Park 3,  Jae-Hyun Park 3,  Woo-Sup Sim 3,  Jin-Ju Kim 3,  Hye Ji Lim 1,  Yeon-Ju Kim 1,  Seung Taek Ji 1,  Woong Bi Jang 1,  Vinoth Kumar Rethineswaran 1,  Le Thi Hong Van 1,  Ly Thanh Truong Giang 1,  Jisoo Yun 1,  Jong Seong Ha 1,  Kiwon Ban 5,  Hae Young Chung 6,  Sang Hong Baek 7,  Hun-Jun Park 8 9,  Sang-Mo Kwon 10
Affiliations

Affiliations

  • 1 Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University, Yangsan, 50612, Republic of Korea.
  • 2 R&D Center for Advanced Pharmaceuticals & Evaluation, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea.
  • 3 Department of Medical Life Science, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-Gu, Seoul, 137701, Republic of Korea.
  • 4 Laboratory of Medicinal Chemistry, College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
  • 5 Department of Biomedical Sciences, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR.
  • 6 Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Busan, 462414, Republic of Korea.
  • 7 Division of Cardiology, Department of Internal Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-Gu, Seoul, 137701, Republic of Korea. whitesh@catholic.ac.kr.
  • 8 Department of Medical Life Science, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-Gu, Seoul, 137701, Republic of Korea. cardioman@catholic.ac.kr.
  • 9 Division of Cardiology, Department of Internal Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-Gu, Seoul, 137701, Republic of Korea. cardioman@catholic.ac.kr.
  • 10 Laboratory for Vascular Medicine and Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University, Yangsan, 50612, Republic of Korea. smkwon323@hotmail.com.
  • # Contributed equally.
PMID: 34584195 DOI: 10.1038/s12276-021-00676-x
Abstract

Stem cell-based therapies with clinical applications require millions of cells. Therefore, repeated subculture is essential for cellular expansion, which is often complicated by replicative senescence. Cellular senescence contributes to reduced stem cell regenerative potential as it inhibits stem cell proliferation and differentiation as well as the activation of the senescence-associated secretory phenotype (SASP). In this study, we employed MHY-1685, a novel mammalian target of rapamycin (mTOR) inhibitor, and examined its long-term priming effect on the activities of senile human cardiac stem cells (hCSCs) and the functional benefits of primed hCSCs after transplantation. In vitro experiments showed that the MHY-1685‒primed hCSCs exhibited higher viability in response to oxidative stress and an enhanced proliferation potential compared to that of the unprimed senile hCSCs. Interestingly, priming MHY-1685 enhanced the expression of stemness-related markers in senile hCSCs and provided the differentiation potential of hCSCs into vascular lineages. In vivo experiment with echocardiography showed that transplantation of MHY-1685‒primed hCSCs improved cardiac function than that of the unprimed senile hCSCs at 4 weeks post-MI. In addition, hearts transplanted with MHY-1685-primed hCSCs exhibited significantly lower cardiac fibrosis and higher capillary density than that of the unprimed senile hCSCs. In confocal fluorescence imaging, MHY-1685‒primed hCSCs survived for longer durations than that of the unprimed senile hCSCs and had a higher potential to differentiate into endothelial cells (ECs) within the infarcted hearts. These findings suggest that MHY-1685 can rejuvenate senile hCSCs by modulating Autophagy and that as a senescence inhibitor, MHY-1685 can provide opportunities to improve hCSC-based myocardial regeneration.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-141805
    99.97%, mTOR Inhibitor