{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T05:40:54Z","timestamp":1774590054108,"version":"3.50.1"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":4,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020275","name":"Vilnius University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020275","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Mesenchymal stromal cells (MSCs) of various origins promote regeneration through paracrine signaling, immune modulation, and angiogenesis support. Premature ovarian failure (POF) is an excellent model to study coordinated ovarian and uterine repair, as cytotoxic injury simultaneously depletes ovarian follicles and impairs uterine receptors, resulting in infertility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We established a busulfan\/cyclophosphamide (Bu\/Cy) POF model and applied human MSCs derived from reproductive\/perinatal tissues\u2014endometrium (hEndSCs), menstrual blood (hMenSCs), placenta (hPSCs), or follicular fluid (hFFSCs)\u2014to treat the condition. The primary endpoint was pregnancy rate; secondary endpoints included serum anti-Mullerian hormone (AMH) levels and ovarian\/uterine molecular profiles (RT-qPCR panels; selected ovarian signaling proteins by Western blot).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Chemotherapy reduced fertility (0%) and AMH levels compared to healthy controls. MSC therapy restored fertility in 41%\u201375% of mice, with hEndSC and hMenSC achieving the highest pregnancy rates (both 75%) and the highest AMH recovery. In the ovary, MSC increased Amh, Gdf3, Gja1, Zp1, and, depending on the source, Fshr, with concomitant activation of PI3K\/AKT\/mTOR effectors (p-AKT, p-mTOR, p-GSK3\u03b2, p-PDK1). In the uterus, MSC increased the expression of Col1a1, Col3a1, Ctgf, Pcna, Ccnd1, and Ki67, consistent with extracellular matrix repair and proliferative renewal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data suggest that MSCs derived from reproductive tissues, particularly endometrial origin, may restore fertility in POI by linking follicular activation to endometrial remodeling and support the translational development of MSC therapies that address both follicular depletion and uterine competence in infertility.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/stcltm\/szag013","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T03:54:28Z","timestamp":1774583668000},"source":"Crossref","is-referenced-by-count":0,"title":["Reproductive tissue\u2013derived stromal cells rescue fertility by coupling follicular activation with endometrial remodeling"],"prefix":"10.1093","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6077-0136","authenticated-orcid":false,"given":"Veronika Viktorija","family":"Borutinskait\u0117","sequence":"first","affiliation":[{"name":"Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University , Vilnius, LT-01257, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Indr\u0117","family":"Krastinait\u0117","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University , Vilnius, LT-01257, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elvina","family":"Valatkait\u0117","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University , Vilnius, LT-01257, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aist\u0117","family":"Zentelyt\u0117-Vilk\u0117","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University , Vilnius, LT-01257, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R\u016bta","family":"Navakauskien\u0117","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University , Vilnius, LT-01257, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"2026032623542063300_szag013-B1","doi-asserted-by":"crossref","first-page":"823","DOI":"10.3390\/ijms20040823","article-title":"Unveiling mesenchymal stromal cells\u2019 organizing function in regeneration","volume":"20","author":"Nimiritsky","year":"2019","journal-title":"Int J Mol Sci"},{"key":"2026032623542063300_szag013-B2","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1007\/s00109-021-02055-5","article-title":"Premature ovarian insufficiency: pathogenesis and therapeutic potential of mesenchymal stem cell","volume":"99","author":"Takahashi","year":"2021","journal-title":"J Mol Med (Berl)"},{"key":"2026032623542063300_szag013-B3","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1055\/s-0040-1722317","article-title":"Prevalence and risk factors of premature ovarian insufficiency\/early menopause","volume":"38","author":"Giri","year":"2020","journal-title":"Semin Reprod Med"},{"key":"2026032623542063300_szag013-B4","doi-asserted-by":"crossref","first-page":"300060520932403","DOI":"10.1177\/0300060520932403","article-title":"Psychological aspects of infertility","volume":"48","author":"Szkodziak","year":"2020","journal-title":"J Int Med Res"},{"key":"2026032623542063300_szag013-B5","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1080\/13697137.2022.2153033","article-title":"The global prevalence of premature ovarian insufficiency: a systematic review and meta-analysis","volume":"26","author":"Li","year":"2023","journal-title":"Climacteric"},{"key":"2026032623542063300_szag013-B6","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1210\/clinem\/dgac039","article-title":"Evaluation of female fertility\u2014AMH and ovarian reserve testing","volume":"107","author":"Cedars","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"2026032623542063300_szag013-B7","doi-asserted-by":"crossref","first-page":"101561","DOI":"10.1016\/j.beem.2021.101561","article-title":"Hormone therapy regimens for managing the menopause and premature ovarian insufficiency","volume":"35","author":"Armeni","year":"2021","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2026032623542063300_szag013-B8","doi-asserted-by":"crossref","first-page":"572388","DOI":"10.3389\/fendo.2020.572388","article-title":"Chemotherapy associated ovarian failure","volume":"11","author":"Mauri","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2026032623542063300_szag013-B9","doi-asserted-by":"crossref","first-page":"795724","DOI":"10.3389\/fendo.2021.795724","article-title":"Live birth rate in patients with premature ovarian insufficiency during long-term follow-up under hormone replacement with or without ovarian stimulation","volume":"12","author":"Ishizuka","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2026032623542063300_szag013-B10","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.bpobgyn.2021.09.011","article-title":"Premature ovarian insufficiency","volume":"81","author":"McGlacken-Byrne","year":"2022","journal-title":"Best Pract Res Clin Obstet Gynaecol"},{"key":"2026032623542063300_szag013-B11","doi-asserted-by":"crossref","first-page":"672890","DOI":"10.3389\/fcell.2021.672890","article-title":"Premature ovarian insufficiency: past, present, and future","volume":"9","author":"Chon","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"2026032623542063300_szag013-B12","doi-asserted-by":"crossref","first-page":"e2693","DOI":"10.21769\/BioProtoc.2693","article-title":"Human endometrial stem cell isolation from endometrium and menstrual blood","volume":"8","author":"Tavakol","year":"2018","journal-title":"Bio Protoc"},{"key":"2026032623542063300_szag013-B13","doi-asserted-by":"crossref","first-page":"765265","DOI":"10.3389\/fcell.2021.765265","article-title":"Decidualization potency and epigenetic changes in human endometrial origin stem cells during propagation","volume":"9","author":"Valatkait\u0117","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"2026032623542063300_szag013-B14","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.3390\/ijms24032450","article-title":"The effects of the follicle-stimulating hormone on human follicular fluid-derived stromal cells","volume":"24","author":"Skliut\u0117","year":"2023","journal-title":"Int J Mol Sci"},{"key":"2026032623542063300_szag013-B15","doi-asserted-by":"crossref","first-page":"6774","DOI":"10.3390\/ijms22136774","article-title":"Isolation of human menstrual blood\u2013derived mesenchymal stromal cells","volume":"22","author":"Skliut\u0117","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2026032623542063300_szag013-B16","doi-asserted-by":"crossref","first-page":"1140781","DOI":"10.3389\/fbioe.2023.1140781","article-title":"Effects of human placenta cryopreservation on molecular characteristics of placental mesenchymal stromal cells","volume":"11","author":"Navakauskien\u0117","year":"2023","journal-title":"Front Bioeng Biotechnol"},{"key":"2026032623542063300_szag013-B17","doi-asserted-by":"crossref","first-page":"2098749","DOI":"10.1155\/2019\/2098749","article-title":"High proliferative placenta-derived multipotent cells express cytokeratin 7 at low level","volume":"2019","author":"Shablii","year":"2019","journal-title":"Biomed Res Int"},{"key":"2026032623542063300_szag013-B18","doi-asserted-by":"crossref","first-page":"1227487","DOI":"10.3389\/fcell.2023.1227487","article-title":"Human endometrium-derived mesenchymal stem\/stromal cells application in endometrial-factor induced infertility","volume":"11","author":"Bau\u0161yt\u0117","year":"2023","journal-title":"Front Cell Dev Biol"},{"key":"2026032623542063300_szag013-B19","doi-asserted-by":"crossref","first-page":"409","DOI":"10.15388\/Informatica.2010.297","article-title":"Treatment of over-saturated protein spots in two-dimensional electrophoresis gel images","volume":"21","author":"Serackis","year":"2010","journal-title":"INFORMATICA"},{"key":"2026032623542063300_szag013-B20","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"2026032623542063300_szag013-B21","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s13224-020-01362-0","article-title":"AMH AND its clinical implications","volume":"70","author":"Shrikhande","year":"2020","journal-title":"J Obstet Gynaecol India"},{"key":"2026032623542063300_szag013-B22","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.12659\/MSM.899830","article-title":"Expression pattern of mouse vasa homologue (MVH) in the ovaries of C57BL\/6 female mice","volume":"22","author":"Song","year":"2016","journal-title":"Med Sci Monit"},{"key":"2026032623542063300_szag013-B23","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/bs.vh.2018.01.015","article-title":"Involvement of bone morphogenetic proteins in the regulation of ovarian function","volume":"107","author":"Regan","year":"2018","journal-title":"Vitam Horm"},{"key":"2026032623542063300_szag013-B24","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/s13048-021-00880-3","article-title":"An overview of FSH\u2013FSHR biology and explaining the existing conundrums","volume":"14","author":"Bhartiya","year":"2021","journal-title":"J Ovarian Res"},{"key":"2026032623542063300_szag013-B25","doi-asserted-by":"crossref","first-page":"692","DOI":"10.3389\/fendo.2019.00692","article-title":"Role of mTOR signaling in female reproduction","volume":"10","author":"Guo","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2026032623542063300_szag013-B26","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1093\/biolre\/ioac099","article-title":"MTOR-mediated interaction between the oocyte and granulosa cells regulates the development and function of both compartments in mice","volume":"107","author":"Su","year":"2022","journal-title":"Biol Reprod"},{"key":"2026032623542063300_szag013-B27","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12915-019-0641-9","article-title":"GSK-3\u03b2 protects fetal oocytes from premature death via modulating TAp63 expression in mice","volume":"17","author":"Wen","year":"2019","journal-title":"BMC Biol"},{"key":"2026032623542063300_szag013-B28","first-page":"647","article-title":"Deficiency of PDK1 contributes to primordial follicle activation via upregulation of YAP expression and the pro-inflammatory response","volume":"45","author":"Gao","year":"2020","journal-title":"Int J Mol Med"},{"key":"2026032623542063300_szag013-B29","doi-asserted-by":"crossref","first-page":"9838","DOI":"10.3390\/ijms22189838","article-title":"PI3K\/PTEN\/AKT signaling pathways in germ cell development and their involvement in germ cell tumors and ovarian dysfunctions","volume":"22","author":"De Felici","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2026032623542063300_szag013-B30","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1038\/s41467-018-04848-8","article-title":"Uterine glands coordinate on-time embryo implantation and impact endometrial decidualization for pregnancy success","volume":"9","author":"Kelleher","year":"2018","journal-title":"Nat Commun"},{"key":"2026032623542063300_szag013-B31","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1093\/humrep\/13.suppl_3.247","article-title":"Endometrial integrins and the establishment of uterine receptivity","volume":"13","author":"Lessey","year":"1998","journal-title":"Hum Reprod"},{"key":"2026032623542063300_szag013-B32","doi-asserted-by":"crossref","first-page":"106","DOI":"10.3390\/biom15010106","article-title":"Endometrial receptivity-lessons from \u201comics","volume":"15","author":"Ye","year":"2025","journal-title":"Biomolecules"},{"key":"2026032623542063300_szag013-B33","doi-asserted-by":"crossref","first-page":"S24","DOI":"10.1186\/1755-1536-5-S1-S24","article-title":"CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis","volume":"5","author":"Lipson","year":"2012","journal-title":"Fibrogenesis Tissue Repair"},{"key":"2026032623542063300_szag013-B34","doi-asserted-by":"crossref","first-page":"108895","DOI":"10.1016\/j.abb.2021.108895","article-title":"Adipose-derived stem cell\u2013induced tissue repair is mediated by miR-21\/miR-29b and activation of AKT signaling","volume":"705","author":"Liu","year":"2021","journal-title":"Arch Biochem Biophys"},{"key":"2026032623542063300_szag013-B35","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1007\/s12015-023-10549-7","article-title":"Exosomes from human umbilical cord mesenchymal stem cells facilitate injured endometrial restoring in early repair period through miR-202-3p","volume":"19","author":"Wang","year":"2023","journal-title":"Stem Cell Rev Rep"},{"key":"2026032623542063300_szag013-B36","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1186\/s13287-021-02620-2","article-title":"Stem cell\u2013based therapy for ameliorating intrauterine adhesion and endometrium injury","volume":"12","author":"Song","year":"2021","journal-title":"Stem Cell Res Ther"},{"key":"2026032623542063300_szag013-B37","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s40659-024-00484-3","article-title":"Endometrial mesenchymal stromal\/stem cells improve regeneration of injured endometrium in mice","volume":"57","author":"Li","year":"2024","journal-title":"Biol Res"},{"key":"2026032623542063300_szag013-B38","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/978-1-4939-3584-0_7","article-title":"Paracrine mechanisms of mesenchymal stem cells in tissue repair","volume":"1416","author":"Gnecchi","year":"2016","journal-title":"Methods Mol Biol"},{"key":"2026032623542063300_szag013-B39","doi-asserted-by":"crossref","first-page":"339","DOI":"10.3389\/fimmu.2017.00339","article-title":"Antimicrobial activity of mesenchymal stem cells: current status and new perspectives of antimicrobial peptide-based therapies","volume":"8","author":"Alcayaga-Miranda","year":"2017","journal-title":"Front Immunol"},{"key":"2026032623542063300_szag013-B40","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/1479-5876-6-45","article-title":"Allogeneic endometrial regenerative cells: an \"off the shelf solution\" for critical limb ischemia?","volume":"6","author":"Murphy","year":"2008","journal-title":"J Transl Med"},{"key":"2026032623542063300_szag013-B41","doi-asserted-by":"crossref","first-page":"143466","DOI":"10.1016\/j.chemosphere.2024.143466","article-title":"Early pregnancy exposure to microcystin-LR compromises endometrial decidualization via the PI3K\/AKT\/FOXO1 signaling pathway","volume":"366","author":"Yan","year":"2024","journal-title":"Chemosphere"},{"key":"2026032623542063300_szag013-B42","doi-asserted-by":"crossref","first-page":"e70022","DOI":"10.1111\/aji.70022","article-title":"Mechanism of endometrial receptivity affected by fibroids","volume":"92","author":"Sun","year":"2024","journal-title":"Am J Reprod Immunol"},{"key":"2026032623542063300_szag013-B43","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/mrd.23569","article-title":"CD55 is upregulated by cAMP\/PKA\/AKT and modulates human decidualization via Src and ERK pathway and decidualization-related genes","volume":"89","author":"Tang","year":"2022","journal-title":"Mol Reprod Dev"},{"key":"2026032623542063300_szag013-B44","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1177\/1933719118802056","article-title":"Decidualization of human endometrial stromal fibroblasts is a multiphasic process involving distinct transcriptional programs","volume":"26","author":"Rytk\u00f6nen","year":"2019","journal-title":"Reprod Sci"},{"key":"2026032623542063300_szag013-B45","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1080\/09513590.2019.1680627","article-title":"PI3K\/AKT pathway is altered in the endometriosis patient\u2019s endometrium and presents differences according to severity stage","volume":"36","author":"Madanes","year":"2020","journal-title":"Gynecol Endocrinol"},{"key":"2026032623542063300_szag013-B46","doi-asserted-by":"crossref","first-page":"8069898","DOI":"10.1155\/2019\/8069898","article-title":"Inflamm-aging: a new mechanism affecting premature ovarian insufficiency","volume":"2019","author":"Huang","year":"2019","journal-title":"J Immunol Res"}],"container-title":["Stem Cells Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/15\/4\/szag013\/67558256\/szag013.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/15\/4\/szag013\/67558256\/szag013.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T03:54:35Z","timestamp":1774583675000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stcltm\/article\/doi\/10.1093\/stcltm\/szag013\/8542462"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,23]]},"references-count":46,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,3,23]]}},"URL":"https:\/\/doi.org\/10.1093\/stcltm\/szag013","relation":{},"ISSN":["2157-6564","2157-6580"],"issn-type":[{"value":"2157-6564","type":"print"},{"value":"2157-6580","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,4]]},"published":{"date-parts":[[2026,3,23]]},"article-number":"szag013"}}