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However, the molecular mechanisms behind such a transition in the thymus remain obscure. Using single-cell RNA sequencing (scRNA-seq) of the murine thymic stroma, we identified that major transcriptomic changes occur in the endothelium and mesenchyme across the transition to homeostasis. Differentially expressed gene and intercellular network analyses of temporally resolved scRNA-seq data revealed fibroblast-derived insulin-like growth factor 2 (IGF2) as a candidate driving neonatal thymic expansion. We demonstrated that IGF2 activity promotes a cortical thymic epithelial cell-specific proliferation and is tightly regulated at the thymic growth transition. Bulk RNA-seq of human thymi across the transition also revealed that IGF2 drives thymic expansion, suggesting an evolutionarily conserved role. Our study highlights the role of fibroblast-derived IGF2 in promoting cortical thymic epithelial cell proliferation and differentiation, resulting in early thymic expansion that is followed by downregulation to establish homeostasis.<\/jats:p>","DOI":"10.1242\/dev.204347","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T11:21:28Z","timestamp":1742469688000},"source":"Crossref","is-referenced-by-count":3,"title":["Insulin-like growth factor 2 as a driving force for exponential expansion and differentiation of the neonatal thymus"],"prefix":"10.1242","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4328-5683","authenticated-orcid":false,"given":"Seung Woo","family":"Kang","sequence":"first","affiliation":[{"name":"The University of Georgia 1 Department of Genetics , , Athens, GA 30602 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan R.","family":"Helm","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center 2 Department of Biostatistics , , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center 2 Department of Biostatistics , , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyun","family":"Xiao","sequence":"additional","affiliation":[{"name":"The University of Georgia 1 Department of Genetics , , Athens, GA 30602 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhang","sequence":"additional","affiliation":[{"name":"The University of Georgia 1 Department of Genetics , , Athens, GA 30602 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anusha","family":"Vasudev","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center 3 Department of Epigenetics and Molecular Carcinogenesis , , Houston, TX 77030 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken S.","family":"Lau","sequence":"additional","affiliation":[{"name":"Vanderbilt University School of Medicine 4 Epithlielial Biology Center and Department of Cell and Developmental Biology , , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Liu","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center 2 Department of Biostatistics , , Nashville, TN 37232 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen R.","family":"Richie","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center 3 Department of Epigenetics and Molecular Carcinogenesis , , Houston, TX 77030 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura P.","family":"Hale","sequence":"additional","affiliation":[{"name":"Duke University School of Medicine 5 Department of Pathology and the Human Vaccine Institute , , Durham, NC 27710 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8489-7764","authenticated-orcid":false,"given":"Nancy R.","family":"Manley","sequence":"additional","affiliation":[{"name":"The University of Georgia 1 Department of Genetics , , Athens, GA 30602 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2025,4,10]]},"reference":[{"key":"2025041005225311900_DEV204347C1","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.4049\/jimmunol.146.5.1387","article-title":"Developmental regulation of the intrathymic T cell precursor population","volume":"146","author":"Adkins","year":"1991","journal-title":"J. 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