| Autor: |
Bhalla P; Department of Immunology., Du Q; Department of Immunology., Kumar A; Eugene McDermott Center for Human Growth and Development., Xing C; Eugene McDermott Center for Human Growth and Development.; Departments of Bioinformatics and.; Population and Data Sciences, Departments of., Moses A; Department of Immunology., Dozmorov I; Department of Immunology., Wysocki CA; Pediatrics.; Internal Medicine., Cleaver OB; Molecular Biology, and., Pirolli TJ; Division of Pediatric Cardiothoracic Surgery, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Markert ML; Departments of Pediatrics and Immunology, Duke University Medical Center, Durham, North Carolina, USA., de la Morena MT; Division of Immunology, Department of Pediatrics, University of Washington, and Seattle Children's Hospital, Seattle, Washington, USA., Baldini A; Department Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy., van Oers NS; Department of Immunology.; Pediatrics.; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA. |
| Abstrakt: |
22q11.2 deletion syndrome (22q11.2DS) is the most common human chromosomal microdeletion, causing developmentally linked congenital malformations, thymic hypoplasia, hypoparathyroidism, and/or cardiac defects. Thymic hypoplasia leads to T cell lymphopenia, which most often results in mild SCID. Despite decades of research, the molecular underpinnings leading to thymic hypoplasia in 22q11.2DS remain unknown. Comparison of embryonic thymuses from mouse models of 22q11.2DS (Tbx1neo2/neo2) revealed proportions of mesenchymal, epithelial, and hematopoietic cell types similar to those of control thymuses. Yet, the small thymuses were growth restricted in fetal organ cultures. Replacement of Tbx1neo2/neo2 thymic mesenchymal cells with normal ones restored tissue growth. Comparative single-cell RNA-Seq of embryonic thymuses uncovered 17 distinct cell subsets, with transcriptome differences predominant in the 5 mesenchymal subsets from the Tbx1neo2/neo2 cell line. The transcripts affected included those for extracellular matrix proteins, consistent with the increased collagen deposition we observed in the small thymuses. Attenuating collagen cross-links with minoxidil restored thymic tissue expansion for hypoplastic lobes. In colony-forming assays, the Tbx1neo2/neo2-derived mesenchymal cells had reduced expansion potential, in contrast to the normal growth of thymic epithelial cells. These findings suggest that mesenchymal cells were causal to the small embryonic thymuses in the 22q11.2DS mouse models, which was correctable by substitution with normal mesenchyme. |
