Academic Journal
HOXA3 Knockdown Impairs hESC-Derived Thymic Epithelial-like Cell Differentiation and CXCL12-Associated Early T-Lineage Support.
| Τίτλος: | HOXA3 Knockdown Impairs hESC-Derived Thymic Epithelial-like Cell Differentiation and CXCL12-Associated Early T-Lineage Support. |
|---|---|
| Συγγραφείς: | Shan H; Laboratory of Stem Cells and Translational Medicine, Center for Medical Research on Innovation and Translation, Institute of Clinical Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, China.; Laboratory of Stem Cells and Translational Medicine, Institute for Life Science, School of Medicine, South China University of Technology, Guangzhou 510006, China., Fu Y; Laboratory of Stem Cells and Translational Medicine, Center for Medical Research on Innovation and Translation, Institute of Clinical Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, China.; Laboratory of Stem Cells and Translational Medicine, Institute for Life Science, School of Medicine, South China University of Technology, Guangzhou 510006, China., Shi X; Laboratory of Stem Cells and Translational Medicine, Center for Medical Research on Innovation and Translation, Institute of Clinical Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, China.; Laboratory of Stem Cells and Translational Medicine, Institute for Life Science, School of Medicine, South China University of Technology, Guangzhou 510006, China., Chen S; Laboratory of Stem Cells and Translational Medicine, Center for Medical Research on Innovation and Translation, Institute of Clinical Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, China.; Laboratory of Stem Cells and Translational Medicine, Institute for Life Science, School of Medicine, South China University of Technology, Guangzhou 510006, China., Duan Y; Laboratory of Stem Cells and Translational Medicine, Center for Medical Research on Innovation and Translation, Institute of Clinical Medicine, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, China.; Laboratory of Stem Cells and Translational Medicine, Institute for Life Science, School of Medicine, South China University of Technology, Guangzhou 510006, China.; National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, China.; The Innovation Centre of Ministry of Education for Development and Diseases, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, China. |
| Πηγή: | Cells [Cells] 2026 Sep 27; Vol. 15 (19). Date of Electronic Publication: 2026 Sep 27. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Basel, Switzerland : MDPI |
| Ιατρικοί όροι (MeSH): | Cell Differentiation*/genetics , Epithelial Cells*/metabolism , Epithelial Cells*/cytology , Homeodomain Proteins*/metabolism , Homeodomain Proteins*/genetics , Thymus Gland*/cytology , Chemokine CXCL12*/metabolism , Chemokine CXCL12*/genetics , Human Embryonic Stem Cells*/metabolism , Human Embryonic Stem Cells*/cytology , T-Lymphocytes*/cytology , T-Lymphocytes*/metabolism , Gene Knockdown Techniques* , Cell Lineage*, Humans |
| Περίληψη: | Thymic epithelial cells (TECs) provide essential signals for T-cell development, yet the mechanisms governing human TEC differentiation and the acquisition of T-cell-supporting function remain incompletely understood. Using a three-stage system that directs human embryonic stem cells (hESCs) through definitive endoderm and third pharyngeal pouch endoderm (3PPE) toward a thymic epithelial-like lineage, we investigated the role of HOXA3 during thymic epithelial-like cell (TEC-like cell) differentiation. HOXA3 knockdown during 3PPE-to-TEC-like cell transition impaired thymic epithelial differentiation, as indicated by reduced K8, AIRE, and CD205 expression and decreased FOXN1 protein. HOXA3-knockdown TEC-like cells also showed a markedly reduced capacity to support the generation of CD45+CD3+ cells from cord blood CD34+ progenitors. Bulk RNA sequencing identified 1040 upregulated and 774 downregulated genes, revealing broad remodeling of cell-cycle, motility, chemotaxis, angiogenesis, and tissue-remodeling programs. CXCL12 was among the downregulated genes, and its reduction was confirmed at both mRNA and protein levels. Motif analysis identified a putative HOXA3-binding site, and conventional ChIP-PCR showed enrichment of the predicted CXCL12 regulatory region in HOXA3 immunoprecipitates. Recombinant CXCL12 significantly increased CD45+CD3+ cell generation in HOXA3-knockdown co-cultures. Together, these data support an association between HOXA3 knockdown, reduced acquisition of a thymic epithelial-like phenotype, and diminished early T-lineage support, with CXCL12 partially accounting for the functional phenotype. This study provides a tractable hESC-based model for studying human thymic epithelial development and TEC-mediated early T-lineage differentiation. |
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| Grant Information: | D6201880, K5180910, K5204120, and D6212440 South China University of Technology |
| Contributed Indexing: | Keywords: CXCL12; HOXA3; early T-cell differentiation; human embryonic stem cells; thymic epithelial differentiation; thymic epithelial-like cell |
| Substance Nomenclature: | 0 (Homeodomain Proteins) 0 (Chemokine CXCL12) 0 (HOXA3 protein, human) 0 (CXCL12 protein, human) |
| Entry Date(s): | Date Created: 20261016 Date Completed: 20261016 Latest Revision: 20261020 |
| Update Code: | 20261020 |
| PubMed Central ID: | PMC13664202 |
| DOI: | 10.3390/cells15191764 |
| PMID: | 42882462 |
| Βάση Δεδομένων: | MEDLINE |
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