한빛사논문
Duy‑Cuong Le1,2, Mai‑Huong T. Ngo3, Yung‑Che Kuo4, Shu‑Hwa Chen5, Chung‑Yen Lin6,7,8, Thai‑Yen Ling9, Quoc Thao Trang Pham1, Heng‑Kien Au1,10,11,12*, Jihwan Myung13,14,15* and Yen‑Hua Huang1,3,4,12,15*
1International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
2Laboratory, Vinmec International Hospital, Minh Khai Street, Hai Ba Trung, Hanoi, Vietnam.
3Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan.
4TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan.
5TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.
6Institute of Information Science, Academia Sinica, Taipei 11529, Taiwan.
7Institute of Fishery Sciences, College of Life Science, National Taiwan University, Taipei 10617, Taiwan.
8Genome and Systems Biology Degree Program, National Taiwan University, Taipei 10617, Taiwan.
9Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 10617, Taiwan.
10Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan.
11Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei 11042, Taiwan.
12Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 11042, Taiwan.
13Graduate Institute of Mind, Brain and Consciousness, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan.
14Brain and Consciousness Research Centre (BCRC), TMU-Shuang Ho Hospital, New Taipei City 23561, Taiwan.
15Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Wuxing Street, Taipei 11031, Taiwan.
*Corresponding authors
Correspondence to Heng-Kien Au, Jihwan Myung or Yen-Hua Huang.
Abstract
Background: Primary ovarian insufficiency (POI) is an early decline in ovarian function that leads to ovarian failure. Conventional treatments for POI are inadequate, and treatments based on mesenchymal stem cells (MSCs) have emerged as an option. However, the lack of consideration of the estrogen niche in ovarian tissue significantly reduces the therapeutic efficacy, with an unclear mechanism in the MSCs in POI treatment. Furthermore, the disruption of circadian rhythm associated with POI has not been previously addressed.
Methods: Conditioned medium (CM) and estradiol-conditioned medium (E2-CM) were generated from estrogen receptor positive MSCs (ER+pcMSCs). Chemotherapy-induced POI models were established using C57BL/6 mice (in vivo) and KGN cells (in vitro) treated with cyclophosphamide (CTX) or 4-hydroperoxycyclophosphamide (4-OOH-CP). Gene/protein expressions were detected using RT-qPCR, Western blotting, and immunohistochemistry assays. Locomotor activity was monitored for behavioral circadian rhythmicity. Cytokine arrays and miRNA analysis were conducted to analyze potential factors within CM/E2-CM.
Results: The secretome of ER+pcMSCs (CM and E2-CM) significantly reduced the CTX-induced defects in ovarian folliculogenesis and circadian rhythm. CM/E2-CM also reduced granulosa cell apoptosis and rescued angiogenesis in POI ovarian tissues. E2-CM had a more favorable effect than the CM. Notably, ER+pcMSC secretome restored CTX-induced circadian rhythm defects, including the gene expressions associated with the ovarian circadian clock (e.g., Rora, E4bp4, Rev-erbα, Per2 and Dbp) and locomotor activity. Additionally, the cytokine array analysis revealed a significant increase in cytokines and growth factors associated with immunomodulation and angiogenesis, including angiogenin. Neutralizing the angiogenin in CM/E2-CM significantly reduced its ability to promote HUVEC tube formation in vitro. Exosomal miRNA analysis revealed the miRNAs involved in targeting the genes associated with POI rescue (PTEN and PDCD4), apoptosis (caspase-3, BIM), estrogen synthesis (CYP19A1), ovarian clock regulation (E4BP4, REV-ERBα) and fibrosis (COL1A1).
Conclusion: This study is the first to demonstrate that, in considering the estrogen niche in ovarian tissue, an estrogen-priming ER+pcMSC secretome achieved ovarian regeneration and restored the circadian rhythm in a CTX-induced POI mouse model. The potential factors involved include angiogenin and exosomal miRNAs in the ER+pcMSC secretome. These findings offer insights into potential stem cell therapies for chemotherapy-induced POI and circadian rhythm disruption.
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