{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T09:23:22Z","timestamp":1787304202831,"version":"build-2736575974"},"reference-count":35,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Thin endometrium is a significant cause of infertility due to impaired regeneration, reduced receptivity, and insufficient angiogenesis. Mesenchymal stem cell-derived secretome (MSCsec) is a promising cell-free therapy because it contains bioactive molecules that promote tissue repair. This study evaluated the effects of Wharton\u2019s jelly-derived MSC secretome (WJ-MSCsec) on human endometrial stromal cells (EnSCs) and endothelial cells in vitro. Methods: WJ-MSCs were isolated from umbilical cord tissue, characterized, and cultured under serum-free conditions. The concentrated secretome was analyzed using a human angiogenesis proteome array. EnSCs were isolated from endometrial biopsies. EnSC proliferation and migration in the presence of WJ-MSCsec were assessed using CCK-8 and scratch wound-healing assays. Pro-angiogenic activity of WJ-MSCsec was evaluated using a Matrigel tube formation assay with human umbilical vein endothelial cells (HUVECs). Results: Proteomic analysis of WJ-MSCsec revealed the presence of angiogenic, mitogenic, immunomodulatory, and chemotactic factors. Treatment with WJ-MSCsec significantly enhanced EnSC proliferation and accelerated wound closure. Furthermore, WJ-MSCsec markedly promoted endothelial tube formation, increasing total tube length, junction number, and mesh formation. Conclusions: WJ-MSCsec stimulates EnSC proliferation and migration while enhancing angiogenesis in vitro. WJ-MSCsec represents a promising cell-free therapeutic strategy for endometrial regeneration and reproductive disorders associated with impaired endometrial function.<\/jats:p>","DOI":"10.3390\/cells15161504","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T08:14:01Z","timestamp":1787300041000},"page":"1504","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of Wharton\u2019s Jelly Mesenchymal Stem Cell-Derived Secretome on Cell Functions in Human Endometrium"],"prefix":"10.3390","volume":"15","author":[{"given":"Silviya","family":"Doneva","sequence":"first","affiliation":[{"name":"Tissue Bank BulGen, 1330 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5000-5748","authenticated-orcid":false,"given":"Kalina","family":"Belemezova","sequence":"additional","affiliation":[{"name":"Department of Biology, Medical Faculty, Medical University-Sofia, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vesela","family":"Stoycheva","sequence":"additional","affiliation":[{"name":"Tissue Bank BulGen, 1330 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0939-0685","authenticated-orcid":false,"given":"Ivan","family":"Bochev","sequence":"additional","affiliation":[{"name":"Ob\/Gyn Hospital Dr. Shterev, 1330 Sofia, Bulgaria"},{"name":"Department of Molecular Immunology, Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4042-4038","authenticated-orcid":false,"given":"Tanya","family":"Timeva","sequence":"additional","affiliation":[{"name":"Ob\/Gyn Hospital Dr. Shterev, 1330 Sofia, Bulgaria"},{"name":"Department of Health Care, University of Ruse, 7017 Ruse, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9397-3466","authenticated-orcid":false,"given":"Maria","family":"Yunakova","sequence":"additional","affiliation":[{"name":"Ob\/Gyn Hospital Dr. Shterev, 1330 Sofia, Bulgaria"},{"name":"Department of Obstetrics and Gynecology, Medical Faculty, Medical University-Sofia, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6277-8550","authenticated-orcid":false,"given":"Petya","family":"Andreeva","sequence":"additional","affiliation":[{"name":"Ob\/Gyn Hospital Dr. Shterev, 1330 Sofia, Bulgaria"},{"name":"Department of Health Care, Faculty of Public Health, Health Care and Sports, South-West University Neofit Rilski, 2700 Blagoevgrad, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9434-2867","authenticated-orcid":false,"given":"Katerina","family":"Kavaldzhieva","sequence":"additional","affiliation":[{"name":"Department of Biology, Medical Faculty, Medical University-Sofia, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atanas","family":"Shterev","sequence":"additional","affiliation":[{"name":"Ob\/Gyn Hospital Dr. Shterev, 1330 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanimir","family":"Kyurkchiev","sequence":"additional","affiliation":[{"name":"Tissue Bank BulGen, 1330 Sofia, Bulgaria"},{"name":"Ob\/Gyn Hospital Dr. Shterev, 1330 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal Criteria for Defining Multipotent Mesenchymal Stromal Cells. The International Society for Cellular Therapy Position Statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2638","DOI":"10.1634\/stemcells.2007-0280","article-title":"Molecular and Secretory Profiles of Human Mesenchymal Stromal Cells and Their Abilities to Maintain Primitive Hematopoietic Progenitors","volume":"25","author":"Wagner","year":"2007","journal-title":"Stem Cells"},{"key":"ref_3","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_4","doi-asserted-by":"crossref","first-page":"75","DOI":"10.4103\/1673-5374.264455","article-title":"Mesenchymal Stem Cells Secretome: Current Trends and Future Challenges","volume":"15","author":"Teixeira","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.addr.2012.07.001","article-title":"Mesenchymal Stem Cell: An Efficient Mass Producer of Exosomes for Drug Delivery","volume":"65","author":"Yeo","year":"2013","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.rbmo.2009.12.011","article-title":"Assessment of Presence and Characteristics of Multipotent Stromal Cells in Human Endometrium and Decidua","volume":"20","author":"Kyurkchiev","year":"2010","journal-title":"Reprod. Biomed. Online"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1634\/stemcells.2006-0828","article-title":"Contribution of Bone Marrow-Derived Stem Cells to Endometrium and Endometriosis","volume":"25","author":"Du","year":"2007","journal-title":"Stem Cells"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1111\/j.1479-828X.2004.00290.x","article-title":"Stem Cells in Gynaecology","volume":"44","author":"Gargett","year":"2004","journal-title":"Aust. N. Z. J. Obstet. Gynaecol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1095\/biolreprod.103.024109","article-title":"Clonogenicity of Human Endometrial Epithelial and Stromal Cells1","volume":"70","author":"Chan","year":"2004","journal-title":"Biol. Reprod."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"409","DOI":"10.3109\/09513590.2014.906571","article-title":"Treating Patients with \u201cThin\u201d Endometrium\u2014An Ongoing Challenge","volume":"30","author":"Lebovitz","year":"2014","journal-title":"Gynecol. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1093\/humrep\/deg461","article-title":"The Effect of Endometrial Thickness on IVF\/ICSI Outcome","volume":"18","author":"Kovacs","year":"2003","journal-title":"Hum. Reprod."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ma, J., Gao, W., and Li, D. (2023). Recurrent Implantation Failure: A Comprehensive Summary from Etiology to Treatment. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1061766"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1093\/humupd\/dmu011","article-title":"Endometrial Thickness and Pregnancy Rates after IVF: A Systematic Review and Meta-Analysis","volume":"20","author":"Kasius","year":"2014","journal-title":"Hum. Reprod. Update"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7403","DOI":"10.1002\/jcb.28014","article-title":"Investigation of Platelet-rich Plasma in Increasing Proliferation and Migration of Endometrial Mesenchymal Stem Cells and Improving Pregnancy Outcome of Patients with Thin Endometrium","volume":"120","author":"Wang","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/1754-1611-8-20","article-title":"Endometrial Stem Cells in Regenerative Medicine","volume":"8","author":"Verdi","year":"2014","journal-title":"J. Biol. Eng."},{"key":"ref_16","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-Protocol"},{"key":"ref_17","first-page":"118","article-title":"Regenerative Therapy by Endometrial Mesenchymal Stem Cells in Thin Endometrium with Repeated Implantation Failure. A Novel Strategy","volume":"24","author":"Tersoglio","year":"2019","journal-title":"JBRA Assist. Reprod."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mawet, M., Perrier d\u2019Hauterive, S., Henry, L., Potorac, I., Kridelka, F., Nisolle, M., and Pintiaux, A. (2021). Restoration of Fertility in Patients with Spontaneous Premature Ovarian Insufficiency: New Techniques under the Microscope. J. Clin. Med., 10.","DOI":"10.3390\/jcm10235647"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1089\/bio.2017.0057","article-title":"The Clinical Applications of Endometrial Mesenchymal Stem Cells","volume":"16","author":"Zuo","year":"2018","journal-title":"Biopreserv. Biobank."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"19","DOI":"10.5530\/ami.2016.1.7","article-title":"Autologous Stem Cells Therapy, The First Baby of Idiopathic Premature Ovarian Failure","volume":"3","author":"Edessy","year":"2016","journal-title":"Acta Med. Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e12938","DOI":"10.1111\/cpr.12938","article-title":"Clinical Analysis of Human Umbilical Cord Mesenchymal Stem Cell Allotransplantation in Patients with Premature Ovarian Insufficiency","volume":"53","author":"Yan","year":"2020","journal-title":"Cell Prolif."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1007\/s11427-017-9272-2","article-title":"Transplantation of UC-MSCs on Collagen Scaffold Activates Follicles in Dormant Ovaries of POF Patients with Long History of Infertility","volume":"61","author":"Ding","year":"2018","journal-title":"Sci. China Life Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13048-020-00743-3","article-title":"Evaluation of Safety, Feasibility and Efficacy of Intra-Ovarian Transplantation of Autologous Adipose Derived Mesenchymal Stromal Cells in Idiopathic Premature Ovarian Failure Patients: Non-Randomized Clinical Trial, Phase I, First in Human","volume":"14","author":"Mashayekhi","year":"2021","journal-title":"J. Ovarian Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.4252\/wjsc.v12.i12.1529","article-title":"Mesenchymal Stem Cells Secretome: The Cornerstone of Cell-Free Regenerative Medicine","volume":"12","author":"Dotta","year":"2020","journal-title":"World J. Stem Cells"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.cellbi.2007.12.007","article-title":"Mesenchymal Stem Cells from Human Bone Marrow or Adipose Tissue Differently Modulate Mitogen-stimulated B-cell Immunoglobulin Production in Vitro","volume":"32","author":"Bochev","year":"2008","journal-title":"Cell Biol. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1530\/REP-07-0428","article-title":"Characterization of Clonogenic Stromal Cells Isolated from Human Endometrium","volume":"135","author":"Dimitrov","year":"2008","journal-title":"Reproduction"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11568","DOI":"10.1038\/s41598-020-67289-8","article-title":"Angiogenesis Analyzer for ImageJ\u2014A Comparative Morphometric Analysis of \u201cEndothelial Tube Formation Assay\u201d and \u201cFibrin Bead Assay\u201d","volume":"10","author":"Carpentier","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_28","first-page":"1203","article-title":"A Study of the Transformation of Umbilical Cord Mesenchymal Stem Cells by Interferon-Gamma","volume":"24","author":"Belemezova","year":"2021","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.cellbi.2008.02.002","article-title":"Characterization of Mesenchymal Stem Cells Isolated from the Human Umbilical Cord","volume":"32","author":"Kestendjieva","year":"2008","journal-title":"Cell Biol. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1080\/14712598.2022.2016695","article-title":"Mechanism of Action of Mesenchymal Stem Cells (MSCs): Impact of Delivery Method","volume":"22","author":"Bagno","year":"2022","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41536-019-0070-y","article-title":"Proteomic Analysis of Human Mesenchymal Stromal Cell Secretomes: A Systematic Comparison of the Angiogenic Potential","volume":"4","author":"Kehl","year":"2019","journal-title":"npj Regen. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3571","DOI":"10.1096\/fj.08-111401","article-title":"VEGF Blockade Inhibits Angiogenesis and Reepithelialization of Endometrium","volume":"22","author":"Fan","year":"2008","journal-title":"FASEB J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1530\/REP-22-0485","article-title":"Mesenchymal Stem Cell Secretome Alters Gene Expression and Upregulates Motility of Human Endometrial Stromal Cells","volume":"166","author":"Zhao","year":"2023","journal-title":"Reproduction"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"45200","DOI":"10.18632\/oncotarget.16778","article-title":"Mesenchymal Stem Cells Release Exosomes That Transfer miRNAs to Endothelial Cells and Promote Angiogenesis","volume":"8","author":"Gong","year":"2017","journal-title":"Oncotarget"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s12014-024-09521-5","article-title":"Repair Effect Analysis of Mesenchymal Stem Cell Conditioned Media from Multiple Sources on HUVECs Damaged by High Glucose","volume":"21","author":"Guo","year":"2024","journal-title":"Clin. Proteom."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/16\/1504\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T08:26:22Z","timestamp":1787300782000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/16\/1504"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,21]]},"references-count":35,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cells15161504"],"URL":"https:\/\/doi.org\/10.3390\/cells15161504","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,21]]}}}