{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:44:48Z","timestamp":1785415488198,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T00:00:00Z","timestamp":1778371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2023-00279247"],"award-info":[{"award-number":["RS-2023-00279247"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2023-00279247"],"award-info":[{"award-number":["RS-2023-00279247"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Ministry of Health and Welfare, Republic of Korea","award":["RS-2025-02214065"],"award-info":[{"award-number":["RS-2025-02214065"]}]},{"award":["RS-2025-02214065"],"award-info":[{"award-number":["RS-2025-02214065"]}],"id":[{"id":"https:\/\/ror.org\/00vxgjw72","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Ovarian dysfunction resulting from metabolic or toxic injury is characterized by follicular depletion, stromal remodeling, oxidative stress, and endocrine dysregulation. Placenta-derived mesenchymal stem cells (PD-MSCs) have been proposed as a potential therapeutic approach due to their paracrine factors, including placental growth factor (PlGF). However, the pathways through which PD-MSCs exert protective effects on the ovary remain insufficiently defined. In this study, we examined whether PD-MSC transplantation ameliorates ovarian injury in a thioacetamide (TAA)-induced ovarian insufficiency model and explored the signaling events potentially associated with this response. Female rats were administered TAA for 12 weeks, and PD-MSCs were transplanted at week 8. We assessed ovarian morphology, fibrosis, oxidative stress markers, hormonal profiles, and follicle development. Complementary in vitro experiments using TAA-treated KGN granulosa-like cells were performed to investigate potential mechanistic associations. PD-MSC transplantation improved ovarian architecture, reduced collagen deposition, enhanced follicle growth, and mitigated oxidative stress. These changes were accompanied by increased PlGF expression and enhanced activation of fms-like tyrosine kinase-1 (Flt-1), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and nuclear factor erythroid 2-related factor 2 (Nrf2)-related antioxidant pathways. In vitro, PD-MSCs coculture similarly attenuated oxidative stress and partially improved mitochondrial membrane potential in damaged KGN cells. Together, these findings suggest that PD-MSCs ameliorate ovarian structural damage and oxidative stress in TAA-induced injury, potentially through paracrine mechanisms partly involving PlGF\/Flt-1-associated antioxidant signaling. This work supports the therapeutic potential of PD-MSCs for metabolic or toxicant-induced ovarian insufficiency while underscoring the need for further studies to fully delineate the specific contribution of PlGF and its interaction with downstream antioxidant pathways.<\/jats:p>","DOI":"10.3390\/antiox15050603","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T16:39:34Z","timestamp":1779295174000},"page":"603","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Placental Growth Factor Secreted from Placenta-Derived Mesenchymal Stem Cells Improves Ovarian Function in TAA-Injured Rats via Antioxidant Effects"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2818-5130","authenticated-orcid":false,"given":"Jae-Young","family":"Shin","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, CHA University, Pocheon 11160, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae-Hyun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Convergence Science, CHA University, Pocheon 11160, Republic of Korea"},{"name":"Research Institute of Placental Science, CHA University, Pocheon 11160, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2274-5313","authenticated-orcid":false,"given":"Hyeri","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, CHA University, Pocheon 11160, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Ran","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Pocheon 11160, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2320-7157","authenticated-orcid":false,"given":"Gi Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, CHA University, Pocheon 11160, Republic of Korea"},{"name":"Research Institute of Placental Science, CHA University, Pocheon 11160, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Shi, Y.Q., Zhu, X.T., Zhang, S.N., Ma, Y.F., Han, Y.H., Jiang, Y., and Zhang, Y.H. (2023). Premature ovarian insufficiency: A review on the role of oxidative stress and the application of antioxidants. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1172481"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s13048-022-01032-x","article-title":"The role of oxidative stress in ovarian aging: A review","volume":"15","author":"Yan","year":"2022","journal-title":"J. Ovarian Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"eabn4564","DOI":"10.1126\/sciadv.abn4564","article-title":"Female reproductive life span is extended by targeted removal of fibrotic collagen from the mouse ovary","volume":"8","author":"Umehara","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103776","DOI":"10.1016\/j.redox.2025.103776","article-title":"Reactive oxygen species in polycystic ovary syndrome: Mechanistic insights into pathogenesis and therapeutic opportunities","volume":"85","author":"Liu","year":"2025","journal-title":"Redox Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s12958-024-01337-0","article-title":"Oxidative stress and energy metabolism abnormalities in polycystic ovary syndrome: From mechanisms to therapeutic strategies","volume":"22","author":"Yan","year":"2024","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8882368","DOI":"10.1155\/2021\/8882368","article-title":"Mesenchymal Stem Cells in Preclinical Infertility Cytotherapy: A Retrospective Review","volume":"2021","author":"Chang","year":"2021","journal-title":"Stem Cells Int."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Webber, L., Anderson, R.A., Davies, M., Janse, F., and Vermeulen, N. (2017). HRT for women with premature ovarian insufficiency: A comprehensive review. Hum. Reprod. Open, hox007.","DOI":"10.1093\/hropen\/hox007"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Huang, Y., Zhu, M., Liu, Z., Hu, R., Li, F., Song, Y., Geng, Y., Ma, W., Song, K., and Zhang, M. (2022). Bone marrow mesenchymal stem cells in premature ovarian failure: Mechanisms and prospects. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.997808"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/s13287-024-03698-0","article-title":"Efficacy and safety of mesenchymal stem cell therapy for ovarian ageing in a mouse model","volume":"15","author":"Pei","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1634\/stemcells.2007-0594","article-title":"Concise review: Isolation and characterization of cells from human term placenta: Outcome of the first international Workshop on Placenta Derived Stem Cells","volume":"26","author":"Parolini","year":"2008","journal-title":"Stem Cells"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s13287-025-04254-0","article-title":"Mesenchymal stromal\/stem cells from perinatal sources: Biological facts, molecular biomarkers, and therapeutic promises","volume":"16","author":"Allouh","year":"2025","journal-title":"Stem Cell Res. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13578-020-00433-z","article-title":"Perspective of placenta derived mesenchymal stem cells in acute liver failure","volume":"10","author":"Saleh","year":"2020","journal-title":"Cell Biosci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Xie, N., Wang, F., Chen, D., Zhou, J., Xu, J., and Qu, F. (2024). Immune dysfunction mediated by the competitive endogenous RNA network in fetal side placental tissue of polycystic ovary syndrome. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0300461"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"eabc8587","DOI":"10.1126\/scitranslmed.abc8587","article-title":"Evidence for a protective role of placental growth factor in cardiovascular disease","volume":"12","author":"Chen","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16821","DOI":"10.1038\/s41598-021-96256-0","article-title":"Genetics of PlGF plasma levels highlights a role of its receptors and supports the link between angiogenesis and immunity","volume":"11","author":"Ruggiero","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/jhh.2017.61","article-title":"Placental growth factor and pre-eclampsia","volume":"31","author":"Chau","year":"2017","journal-title":"J. Hum. Hypertens."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"a011056","DOI":"10.1101\/cshperspect.a011056","article-title":"PlGF: A multitasking cytokine with disease-restricted activity","volume":"2","author":"Dewerchin","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15339","DOI":"10.1038\/s41598-019-51603-0","article-title":"Distinct downstream signaling and the roles of VEGF and PlGF in high glucose-mediated injuries of human retinal endothelial cells in culture","volume":"9","author":"Jiao","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1093\/toxsci\/kfg083","article-title":"Erk activation is required for Nrf2 nuclear localization during pyrrolidine dithiocarbamate induction of glutamate cysteine ligase modulatory gene expression in HepG2 cells","volume":"73","author":"Zipper","year":"2003","journal-title":"Toxicol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/s41392-024-02095-6","article-title":"Redox regulation: Mechanisms, biology and therapeutic targets in diseases","volume":"10","author":"Li","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1186\/s13048-025-01737-9","article-title":"The roles of MAPK signaling pathway in ovarian folliculogenesis","volume":"18","author":"Zhao","year":"2025","journal-title":"J. Ovarian Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"14994","DOI":"10.1038\/srep14994","article-title":"Functional microarray analysis of differentially expressed genes in granulosa cells from women with polycystic ovary syndrome related to MAPK\/ERK signaling","volume":"5","author":"Lan","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13048-025-01639-w","article-title":"Overview of Nrf2 as a target in ovary and ovarian dysfunctions focusing on its antioxidant properties","volume":"18","author":"Ghantabpour","year":"2025","journal-title":"J. Ovarian Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8099724","DOI":"10.1155\/2022\/8099724","article-title":"Morroniside Protects Human Granulosa Cells against H2O2-Induced Oxidative Damage by Regulating the Nrf2 and MAPK Signaling Pathways","volume":"2022","author":"Ma","year":"2022","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Park, H., Seok, J., You, J.H., Lee, D.H., Lim, J.Y., and Kim, G.J. (2022). Can a Large Number of Transplanted Mesenchymal Stem Cells Have an Optimal Therapeutic Effect on Improving Ovarian Function?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232416009"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Seok, J., Park, H., Lee, D.H., You, J.H., and Kim, G.J. (2023). The Dose-Related Efficacy of Human Placenta-Derived Mesenchymal Stem Cell Transplantation on Antioxidant Effects in a Rat Model with Ovariectomy. Antioxidants, 12.","DOI":"10.3390\/antiox12081575"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1002\/jcb.22873","article-title":"Anti-fibrotic effect of chorionic plate-derived mesenchymal stem cells isolated from human placenta in a rat model of CCl4-injured liver: Potential application to the treatment of hepatic diseases","volume":"111","author":"Lee","year":"2010","journal-title":"J. Cell Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., and Dirnagl, U. (2020). The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000410"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1530\/rep.1.00095","article-title":"Methods for quantifying follicular numbers within the mouse ovary","volume":"127","author":"Myers","year":"2004","journal-title":"Reproduction"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"104093","DOI":"10.1016\/j.etap.2023.104093","article-title":"Molecular mechanisms in thioacetamide-induced acute and chronic liver injury models","volume":"99","author":"Ezhilarasan","year":"2023","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13048-017-0375-7","article-title":"DHEA-induced ovarian hyperfibrosis is mediated by TGF-\u03b2 signaling pathway","volume":"11","author":"Wang","year":"2018","journal-title":"J. Ovarian Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"61","DOI":"10.18632\/aging.202348","article-title":"Human placenta-derived mesenchymal stem cells trigger repair system in TAA-injured rat model via antioxidant effect","volume":"13","author":"Na","year":"2020","journal-title":"Aging"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ren, Y., Suzuki, H., Jagarlamudi, K., Golnoski, K., McGuire, M., Lopes, R., Pachnis, V., and Rajkovic, A. (2015). Lhx8 regulates primordial follicle activation and postnatal folliculogenesis. BMC Biol., 13.","DOI":"10.1186\/s12915-015-0151-3"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Liu, S., Jia, Y., Meng, S., Luo, Y., Yang, Q., and Pan, Z. (2023). Mechanisms of and Potential Medications for Oxidative Stress in Ovarian Granulosa Cells: A Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119205"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.placenta.2004.05.004","article-title":"Hypoxia-induced increase in soluble Flt-1 production correlates with enhanced oxidative stress in trophoblast cells from the human placenta","volume":"26","author":"Li","year":"2005","journal-title":"Placenta"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Shurubor, Y.I., Rogozhin, A.E., Isakova, E.P., Deryabina, Y.I., and Krasnikov, B.F. (2023). Tricarboxylic Acid Metabolite Imbalance in Rats with Acute Thioacetamide-Induced Hepatic Encephalopathy Indicates Incomplete Recovery. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021384"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s13287-018-0819-z","article-title":"Human chorionic plate-derived mesenchymal stem cells transplantation restores ovarian function in a chemotherapy-induced mouse model of premature ovarian failure","volume":"9","author":"Li","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Guo, C., Ma, Y., Situ, Y., Liu, L., Luo, G., Li, H., Ma, W., Sun, L., Wang, W., and Weng, Q. (2023). Mesenchymal stem cells therapy improves ovarian function in premature ovarian failure: A systematic review and meta-analysis based on preclinical studies. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1165574"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s13287-016-0363-7","article-title":"Mechanisms of mesenchymal stem\/stromal cell function","volume":"7","author":"Spees","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Zhong, Y., Zou, L., and Liu, X. (2022). Significance of Placental Mesenchymal Stem Cell in Placenta Development and Implications for Preeclampsia. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.896531"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e12712","DOI":"10.1111\/cpr.12712","article-title":"Immune modulation by mesenchymal stem cells","volume":"53","author":"Jiang","year":"2020","journal-title":"Cell Prolif."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"55","DOI":"10.21315\/mjms2023.30.2.5","article-title":"Human Mesenchymal Stromal Cells Derived from Perinatal Tissues: Sources, Characteristics and Isolation Methods","volume":"30","author":"Teoh","year":"2023","journal-title":"Malays. J. Med. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Massaro, F., Corrillon, F., Stamatopoulos, B., Dubois, N., Ruer, A., Meuleman, N., Bron, D., and Lagneaux, L. (2023). Age-related changes in human bone marrow mesenchymal stromal cells: Morphology, gene expression profile, immunomodulatory activity and miRNA expression. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1267550"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1479-5876-12-8","article-title":"Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation","volume":"12","author":"Choudhery","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1210\/en.2017-00739","article-title":"Placental Growth Factor Is Required for Ovulation, Luteinization, and Angiogenesis in Primate Ovulatory Follicles","volume":"159","author":"Bender","year":"2018","journal-title":"Endocrinology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6678","DOI":"10.1002\/jcp.30330","article-title":"Human placenta-derived mesenchymal stem cells induce trophoblast invasion via dynamic effects on mitochondrial function","volume":"236","author":"Seok","year":"2021","journal-title":"J. Cell Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kostadinova-Slavova, D., Petkova-Parlapanska, K., Koleva, I., Angelova, M., Al-Dahwi, R.S.J., Georgieva, E., Karamalakova, Y., and Nikolova, G. (2024). Preeclampsia Treatment Aspirin\/Clampsilin: Oxidative Stress, sFlt-1\/PIGF Soluble Tyrosine Kinase 1, and Placental Growth Factor Monitoring. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252413497"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"103682","DOI":"10.1016\/j.jprot.2020.103682","article-title":"Placental growth factor regulates the pentose phosphate pathway and antioxidant defense systems in human retinal endothelial cells","volume":"217","author":"Saddala","year":"2020","journal-title":"J. Proteom."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Shin, S., Lee, J., Kwon, Y., Park, K.S., Jeong, J.H., Choi, S.J., Bang, S.I., Chang, J.W., and Lee, C. (2021). Comparative Proteomic Analysis of the Mesenchymal Stem Cells Secretome from Adipose, Bone Marrow, Placenta and Wharton\u2019s Jelly. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020845"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"829","DOI":"10.3727\/096368915X689622","article-title":"Clinical Trials With Mesenchymal Stem Cells: An Update","volume":"25","author":"Squillaro","year":"2016","journal-title":"Cell Transplant."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/5\/603\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T16:52:09Z","timestamp":1779295929000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/5\/603"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,10]]},"references-count":50,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["antiox15050603"],"URL":"https:\/\/doi.org\/10.3390\/antiox15050603","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,10]]}}}