{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T01:10:42Z","timestamp":1787274642978,"version":"build-2736575974"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>\n                    Mesenchymal stem cells (MSCs) can participate in lymphangiogenesis through paracrine effects, while lymphatic endothelial progenitor cells (LEPCs), a subpopulation of endothelial progenitor cells (EPCs), can differentiate into mature lymphatic endothelial cells, thereby influencing lymphatic function. In the present study, we investigated the mechanism by which MSCs regulate the activity of LEPCs through paracrine effects and preliminarily explored the possibility of the two types of cells working together to treat lymphovascular diseases. After isolation of MSCs and LEPCs from the bone marrow of C57BL\/6\u00a0J mice,\n                    <jats:italic>in vitro<\/jats:italic>\n                    experiments verified that insulin-like growth factor 1 (IGF-1) secreted by MSCs activated the PI3K\/Akt\/mTOR pathway to promote the proliferation of LEPCs; IGF-1 decreased the rate of apoptosis and affected the cycle progression of LEPCs and the nucleotide metabolism levels. The therapeutic efficacy of combined transplantation of MSCs and LEPCs was shown to be superior to that of transplantation of LEPCs alone in murine hindlimb lymphedema models. These results suggest that MSCs significantly promote the proliferation of LEPCs through the activation of the PI3K\/Akt\/mTOR pathway in LEPCs by secreting IGF-1, and that IGF-1 also inhibits apoptosis and regulates cell metabolism. Combined transplantation of MSCs and LEPCs provides an experimental rationale and potential strategy for cell therapy in lymphedema.\n                  <\/jats:p>","DOI":"10.3389\/fgene.2025.1584095","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T01:24:40Z","timestamp":1747790680000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["IGF-1 secreted by mesenchymal stem cells affects the function of lymphatic endothelial progenitor cells: a potential strategy for the treatment of lymphedema"],"prefix":"10.3389","volume":"16","author":[{"given":"Zekuan","family":"Xue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongdong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinchun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzhou","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengqiu","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jixue","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"111816","DOI":"10.1016\/j.yexcr.2020.111816","article-title":"Human adipose-derived stem cells support lymphangiogenesis in vitro by secretion of lymphangiogenic factors","volume":"388","author":"Ahmadzadeh","year":"2020","journal-title":"Exp. Cell Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"381","DOI":"10.3390\/pharmaceutics14020381","article-title":"Mesenchymal stem\/stromal cells and their paracrine activity\u2014immunomodulation mechanisms and how to influence the therapeutic potential","volume":"14","author":"Alvites","year":"2022","journal-title":"Pharmaceutics"},{"key":"B3","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/s41419-017-0082-8","article-title":"Autophagy promotes MSC-mediated vascularization in cutaneous wound healing via regulation of VEGF secretion","volume":"9","author":"An","year":"2018","journal-title":"Cell Death Dis."},{"key":"B4","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1126\/science.275.5302.964","article-title":"Isolation of putative progenitor endothelial cells for angiogenesis","volume":"275","author":"Asahara","year":"1997","journal-title":"Science"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.1038\/onc.2014.155","article-title":"Ribonucleotide reductase and cancer: biological mechanisms and targeted therapies","volume":"34","author":"Aye","year":"2015","journal-title":"Oncogene"},{"key":"B6","doi-asserted-by":"publisher","first-page":"15593","DOI":"10.1073\/pnas.0507865102","article-title":"Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo","volume":"102","author":"Bj\u00f6rndahl","year":"2005","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"261","DOI":"10.3390\/biology10040261","article-title":"Biology of lymphedema","volume":"10","author":"Brix","year":"2021","journal-title":"Biology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1007\/s00018-013-1460-8","article-title":"De novo hem- and lymphangiogenesis by endothelial progenitor and mesenchymal stem cells in immunocompetent mice","volume":"71","author":"Buttler","year":"2014","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"B9","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.actbio.2021.08.005","article-title":"Isolating and characterizing lymphatic endothelial progenitor cells for potential therapeutic lymphangiogenic applications","volume":"135","author":"Campbell","year":"2021","journal-title":"Acta Biomater."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e1886","DOI":"10.1371\/journal.pone.0001886","article-title":"Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing","volume":"3","author":"Chen","year":"2008","journal-title":"PLoS ONE"},{"key":"B11","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1161\/CIRCULATIONAHA.108.793208","article-title":"Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo","volume":"119","author":"Conrad","year":"2009","journal-title":"Circulation"},{"key":"B12","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.yexcr.2015.11.015","article-title":"Isolation and characterization of circulating lymphatic endothelial colony forming cells","volume":"340","author":"DiMaio","year":"2016","journal-title":"Exp. Cell Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e20","DOI":"10.1161\/01.RES.0000205765.28940.93","article-title":"CD34\u2212\/CD133+\/VEGFR-2+ endothelial progenitor cell subpopulation with potent vasoregenerative capacities","volume":"98","author":"Friedrich","year":"2006","journal-title":"Circ. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"20417314221109957","DOI":"10.1177\/20417314221109957","article-title":"Adipose tissue-derived microvascular fragments promote lymphangiogenesis in a murine lymphedema model","volume":"13","author":"Frueh","year":"2022","journal-title":"J. Tissue Eng."},{"key":"B15","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1002\/jcb.20984","article-title":"Insulin\u2010like growth factors induce apoptosis as well as proliferation in LIM 1215 colon cancer cells","volume":"100","author":"Fu","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1089\/ten.TEB.2016.0365","article-title":"Trophic effects of mesenchymal stem cells in tissue regeneration","volume":"23","author":"Fu","year":"2017","journal-title":"Tissue Eng. Part B Rev."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1976","DOI":"10.3892\/ijmm.2018.3424","article-title":"Interleukin-1\u03b2 induces intercellular adhesion molecule-1 expression, thus enhancing the adhesion between mesenchymal stem cells and endothelial progenitor cells via the p38 MAPK signaling pathway","volume":"41","author":"Guo","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1111\/jog.14412","article-title":"miR-483 is downregulated in pre-eclampsia via targeting insulin-like growth factor 1 (IGF1) and regulates the PI3K\/Akt\/mTOR pathway of endothelial progenitor cells","volume":"47","author":"Han","year":"2021","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.3892\/mmr.2017.6741","article-title":"Mesenchymal stem cells promote endothelial progenitor cell proliferation by secreting insulin-like growth factor-1","volume":"16","author":"Hou","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"B20","doi-asserted-by":"publisher","first-page":"301","DOI":"10.2119\/2007-00052.Humpert","article-title":"Insulin stimulates the clonogenic potential of angiogenic endothelial progenitor cells by IGF-1 receptor-dependent signaling","volume":"14","author":"Humpert","year":"2008","journal-title":"Mol. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1089\/lrb.2017.0027","article-title":"Stem cell therapy using bone marrow-derived mononuclear cells in treatment of lower limb lymphedema: a randomized controlled clinical trial","volume":"16","author":"Ismail","year":"2018","journal-title":"Lymphat. Res. Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1186\/s13287-021-02324-7","article-title":"Upregulating CXCR7 accelerates endothelial progenitor cell-mediated endothelial repair by activating Akt\/Keap-1\/Nrf2 signaling in diabetes mellitus","volume":"12","author":"Jiang","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"B23","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1002\/sctm.20-0394","article-title":"Adipose-derived regenerative cells and lipotransfer in alleviating breast cancer-related lymphedema: an open-label phase I trial with 4 years of follow-up","volume":"10","author":"J\u00f8rgensen","year":"2021","journal-title":"Stem Cells Transl. Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.ejcb.2016.02.001","article-title":"Effects of mesenchymal stem cell-derived cytokines on the functional properties of endothelial progenitor cells","volume":"95","author":"Kamprom","year":"2016","journal-title":"Eur. J. Cell Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.coi.2018.04.012","article-title":"Lymphatic endothelial progenitor cells: origins and roles in lymphangiogenesis","volume":"53","author":"Kazenwadel","year":"2018","journal-title":"Curr. Opin. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s13287-016-0296-1","article-title":"Hypoxic conditioned medium from mesenchymal stem cells promotes lymphangiogenesis by regulation of mitochondrial-related proteins","volume":"7","author":"Lee","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"B27","doi-asserted-by":"publisher","first-page":"118572","DOI":"10.1016\/j.lfs.2020.118572","article-title":"Initiation of PI3K\/AKT pathway by IGF-1 decreases spinal cord injury-induced endothelial apoptosis and microvascular damage","volume":"263","author":"Li","year":"2020","journal-title":"Life Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"237","DOI":"10.3892\/mmr.2024.13361","article-title":"Swimming training promotes angiogenesis of endothelial progenitor cells by upregulating IGF1 expression and activating the PI3K\/AKT pathway in type 2 diabetic rats","volume":"30","author":"Li","year":"2024","journal-title":"Mol. Med. Rep."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2182","DOI":"10.1242\/jcs.170373","article-title":"Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a","volume":"129","author":"Liang","year":"2016","journal-title":"J. Cell Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/s13287-019-1544-y","article-title":"IGF-1 enhances BMSC viability, migration, and anti-apoptosis in myocardial infarction via secreted frizzled-related protein 2 pathway","volume":"11","author":"Lin","year":"2020","journal-title":"Stem Cell Res. Ther."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e12390","DOI":"10.1111\/cpr.12390","article-title":"IGF-1 promotes angiogenesis in endothelial cells\/adipose-derived stem cells co-culture system with activation of PI3K\/Akt signal pathway","volume":"50","author":"Lin","year":"2017","journal-title":"Cell Prolif."},{"key":"B32","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1038\/s41419-019-1581-6","article-title":"Cancer-associated fibroblasts promote cisplatin resistance in bladder cancer cells by increasing IGF-1\/ER\u03b2\/Bcl-2 signalling","volume":"10","author":"Long","year":"2019","journal-title":"Cell Death Dis."},{"key":"B33","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1146\/annurev.biochem.75.103004.142443","article-title":"Ribonucleotide reductases","volume":"75","author":"Nordlund","year":"2006","journal-title":"Annu. Rev. Biochem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.tcm.2012.04.002","article-title":"Role of bone marrow-derived lymphatic endothelial progenitor cells for lymphatic neovascularization","volume":"21","author":"Park","year":"2011","journal-title":"Trends cardiovasc. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1126\/science.284.5411.143","article-title":"Multilineage potential of adult human mesenchymal stem cells","volume":"284","author":"Pittenger","year":"1999","journal-title":"Science"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3740","DOI":"10.1111\/jcmm.13590","article-title":"Mesenchymal stem cells promote lymphangiogenic properties of lymphatic endothelial cells","volume":"22","author":"Robering","year":"2018","journal-title":"J. Cell. Mol. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1182\/blood-2002-03-0755","article-title":"VEGFR-3 and CD133 identify a population of CD34+ lymphatic\/vascular endothelial precursor cells","volume":"101","author":"Salven","year":"2003","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1038\/nature04869","article-title":"Ras, PI(3)K and mTOR signalling controls tumour cell growth","volume":"441","author":"Shaw","year":"2006","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1186\/s13287-017-0627-x","article-title":"Adipose stem cells from chronic pancreatitis patients improve mouse and human islet survival and function","volume":"8","author":"Song","year":"2017","journal-title":"Stem Cell Res. Ther."},{"key":"B40","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1097\/SAP.0000000000000084","article-title":"Adipose-derived stem cells promote proliferation, migration, and tube formation of lymphatic endothelial cells in vitro by secreting lymphangiogenic factors","volume":"74","author":"Takeda","year":"2015","journal-title":"Ann. Plast. Surg."},{"key":"B41","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1111\/jcmm.12233","article-title":"CD 34+ VEGFR \u20103+ progenitor cells have a potential to differentiate towards lymphatic endothelial cells","volume":"18","author":"Tan","year":"2014","journal-title":"J. Cell. Mol. Med."},{"key":"B42","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.isci.2019.05.004","article-title":"Mesenchymal stromal cell homing: mechanisms and strategies for improvement","volume":"15","author":"Ullah","year":"2019","journal-title":"iScience"},{"key":"B43","doi-asserted-by":"publisher","first-page":"6661","DOI":"10.2147\/IJN.S141592","article-title":"Autophagy promotes degradation of polyethyleneimine-alginate nanoparticles in endothelial progenitor cells","volume":"12","author":"Wang","year":"2017","journal-title":"Int. J. Nanomedicine"},{"key":"B44","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s13046-016-0339-6","article-title":"EphA1 activation promotes the homing of endothelial progenitor cells to hepatocellular carcinoma for tumor neovascularization through the SDF-1\/CXCR4 signaling pathway","volume":"35","author":"Wang","year":"2016","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3791\/60578","article-title":"A revised method for inducing secondary lymphedema in the hindlimb of mice","author":"Wiinholt","year":"2019","journal-title":"J. Vis. Exp. JoVE"},{"key":"B46","doi-asserted-by":"publisher","first-page":"09636897221107536","DOI":"10.1177\/09636897221107536","article-title":"Extracellular vesicles derived from hypoxia-conditioned adipose-derived mesenchymal stem cells enhance lymphangiogenesis","volume":"31","author":"Yang","year":"2022","journal-title":"Cell Transpl."},{"key":"B47","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1002\/bab.1618","article-title":"Construction of tissue-engineered lymphatic vessel using human adipose derived stem cells differentiated lymphatic endothelial like cells and decellularized arterial scaffold: a preliminary study","volume":"65","author":"Yang","year":"2018","journal-title":"Biotechnol. Appl. Biochem."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.3892\/ol.2015.2868","article-title":"Culture medium of bone marrow-derived human mesenchymal stem cells effects lymphatic endothelial cells and tumor lymph vessel formation","volume":"9","author":"Zhan","year":"2015","journal-title":"Oncol. Lett."},{"key":"B49","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1186\/s12951-023-01886-3","article-title":"Optogenetic engineered umbilical cord MSC-derived exosomes for remodeling of the immune microenvironment in diabetic wounds and the promotion of tissue repair","volume":"21","author":"Zhao","year":"2023","journal-title":"J. Nanobiotechnology"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1584095\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T01:24:41Z","timestamp":1747790681000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1584095\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,21]]},"references-count":49,"alternative-id":["10.3389\/fgene.2025.1584095"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2025.1584095","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,21]]},"article-number":"1584095"}}