Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, MA, USA.
Blood. 2010 Apr 29;115(17):3453-62. doi: 10.1182/blood-2009-10-246694. Epub 2010 Jan 20.
Fanconi anemia (FA) is a genetically heterogeneous, autosomal recessive disorder characterized by pediatric bone marrow failure and congenital anomalies. The effect of FA gene deficiency on hematopoietic development in utero remains poorly described as mouse models of FA do not develop hematopoietic failure and such studies cannot be performed on patients. We have created a human-specific in vitro system to study early hematopoietic development in FA using a lentiviral RNA interference (RNAi) strategy in human embryonic stem cells (hESCs). We show that knockdown of FANCA and FANCD2 in hESCs leads to a reduction in hematopoietic fates and progenitor numbers that can be rescued by FA gene complementation. Our data indicate that hematopoiesis is impaired in FA from the earliest stages of development, suggesting that deficiencies in embryonic hematopoiesis may underlie the progression to bone marrow failure in FA. This work illustrates how hESCs can provide unique insights into human development and further our understanding of genetic disease.
范可尼贫血症（FA）是一种遗传异质性的常染色体隐性疾病，其特征为儿科骨髓衰竭和先天畸形。FA 基因缺陷对胎儿造血发育的影响描述不足，因为 FA 的小鼠模型不会发展为造血衰竭，且此类研究不能在患者身上进行。我们利用慢病毒 RNA 干扰（RNAi）策略在人类胚胎干细胞（hESC）中创建了一个专门用于研究 FA 中早期造血发育的人类特异性体外系统。我们发现，在 hESC 中敲低 FANCA 和 FANCD2 会导致造血命运和祖细胞数量减少，而 FA 基因互补可以挽救这种减少。我们的数据表明，造血在 FA 的最早发育阶段就受到损害，这表明胚胎造血缺陷可能是 FA 发展为骨髓衰竭的基础。这项工作说明了 hESC 如何为人类发育提供独特的见解，并进一步加深我们对遗传疾病的理解。
