Mesenchymal cell replacement corrects thymic hypoplasia in murine models of 22q11.2 deletion syndrome.
Mesenchymal cell replacement corrects thymic hypoplasia in murine models of 22q11.2 deletion syndrome.
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DOI：
10.1172/jci160101
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发表时间：
2022-11-15
影响因子：
15.9
通讯作者：
van Ders, Nicolai S. C.
中科院分区：
文献类型：
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作者：
Bhalla, Pratibha;Du, Qiumei;Kumar, Ashwani;Xing, Chao;Moses, Angela;Dozmorov, Igor;Wysocki, Christian A.;Cleaver, Ondine B.;Pirolli, Timothy J.;Markert, Mary Louise;de la Morena, Maria Teresa;Baldini, Antonio;van Ders, Nicolai S. C.
22q11.2缺失综合征(22q11.2DS)是人类最常见的染色体微缺失，可导致发育相关的先天性畸形、胸腺发育不全、甲状旁腺功能减退和/或心脏缺陷。胸腺发育不良会导致T细胞淋巴细胞减少，这通常会导致轻度SCID。尽管经过几十年的研究，22q11.2DS导致胸腺发育不良的分子基础仍不清楚。比较22q11.2DS小鼠模型(Tbx1ne2/ne2)的胚胎胸腺，发现间充质细胞、上皮细胞和造血细胞类型的比例与对照胸腺相似。然而，在胎儿器官培养中，小胸腺的生长受到限制。用正常胸腺间充质细胞替代Tbx1ne2/ne2胸腺间充质细胞可恢复组织生长。胚胎胸腺的比较单细胞RNA-SEQ发现了17个不同的细胞亚群，其中Tbx1ne2/ne2细胞系的5个间充质亚群存在明显的转录组差异。受影响的转录本包括细胞外基质蛋白的转录本，这与我们在小胸腺中观察到的胶原沉积增加一致。用米诺地尔减弱胶原交联物可恢复发育不良小叶的胸腺组织扩张。在集落形成实验中，与胸腺上皮细胞的正常生长相反，Tbx1ne2/ne2来源的间充质细胞的扩增能力降低。这些结果表明，在22q11.2DS小鼠模型中，间充质细胞是小胚胎胸腺的原因，用正常间充质替代是可以纠正的。
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.
影响因子：
3.7
作者：
Abitbol M;Bossé P;Thomas A;Tiret L
通讯作者：
Tiret L