Department of Neurology and Pediatrics, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA.
Departments of Pediatrics and Cancer Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA.
Nat Commun. 2018 Dec 5;9(1):5180. doi: 10.1038/s41467-018-07630-y.
We previously demonstrated that an integrated XIST transgene can broadly repress one chromosome 21 in Down syndrome (DS) pluripotent cells. Here we address whether trisomy-silencing can normalize cell function and development sufficiently to correct cell pathogenesis, tested in an in vitro model of human fetal hematopoiesis, for which DS cellular phenotypes are best known. XIST induction in four transgenic clones reproducibly corrected over-production of megakaryocytes and erythrocytes, key to DS myeloproliferative disorder and leukemia. A contrasting increase in neural stem and iPS cells shows cell-type specificity, supporting this approach successfully rebalances the hematopoietic developmental program. Given this, we next used this system to extend knowledge of hematopoietic pathogenesis on multiple points. Results demonstrate trisomy 21 expression promotes over-production of CD43 but not earlier CD34/CD43progenitors and indicates this is associated with increased IGF signaling. This study demonstrates proof-of-principle for this epigenetic-based strategy to investigate, and potentially mitigate, DS developmental pathologies.
我们之前已经证明，整合的 XIST 转基因可以广泛抑制唐氏综合征（DS）多能细胞中的一条 21 号染色体。在这里，我们研究了三体基因沉默是否足以纠正细胞发病机制，以纠正细胞发病机制，我们在体外人类胎儿造血模型中进行了测试，该模型是 DS 细胞表型最明显的模型。在四个转基因克隆中诱导 XIST 可重复地纠正巨核细胞和红细胞的过度产生，这是 DS 骨髓增生性疾病和白血病的关键。神经干细胞和 iPS 细胞的对比增加显示出细胞类型的特异性，支持这种方法成功地重新平衡了造血发育程序。鉴于此，我们接下来使用该系统在多个方面扩展对造血发病机制的认识。结果表明，21 三体表达促进了 CD43 的过度产生，但不能促进更早的 CD34/CD43 祖细胞的产生，并表明这与 IGF 信号的增加有关。这项研究证明了这种基于表观遗传的策略具有研究和潜在缓解 DS 发育病理学的原理。
