Abstract：
Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure disorder that often presents at infancy. Progress has been made in revealing causal mutated genes (SBDS and others), ribosome defects, and hematopoietic aberrations in SDS. However, the mechanism underlying the hematopoietic failure remained unknown, and treatment options are limited. Herein, we investigated the onset of SDS embryonic hematopoietic impairments. We generated SDS and control human-derived induced pluripotent stem cells (iPSCs). SDS iPSCs recapitulated the SDS hematological phenotype. Detailed stepwise evaluation of definitive hematopoiesis revealed defects that started at the early emerging hematopoietic progenitor (EHP) stage after mesoderm and hemogenic endothelium were normally induced. Hematopoietic potential of EHPs was markedly reduced, and the introduction of SBDS in SDS iPSCs improved colony formation. Transcriptome analysis revealed reduced expression of ribosome and oxidative phosphorylation-related genes in undifferentiated and differentiated iPSCs. However, certain pathways (e.g., DNA replication) and genes (e.g., CHCHD2) were exclusively or more severely dysregulated in EHPs compared with earlier and later stages. To our knowledge, this study offers for the first time an insight into the embryonic onset of human hematopoietic defects in an inherited bone marrow failure syndrome and reveals cellular and molecular aberrations at critical stages of hematopoietic development toward EHPs.
摘要：
Shwachman-Diamond综合征（SDS）是一种遗传性骨髓衰竭疾病，通常在婴儿期出现。在揭示因果突变基因(SBDS等)方面取得了进展，核糖体缺陷,和SDS中的造血异常。然而,造血功能衰竭的潜在机制仍然未知，和治疗选择是有限的。在这里，我们调查了SDS胚胎造血损伤的发生。我们产生SDS和控制人源诱导多能干细胞(iPSC)。SDSiPSC概括了SDS血液学表型。对确定的造血功能的详细逐步评估显示，缺陷始于正常诱导中胚层和生血内皮后的早期造血祖细胞（EHP）阶段。EHP的造血潜能明显降低，在SDS中引入SBDS可以改善iPSCs的集落形成。转录组分析显示未分化和分化的iPSC中核糖体和氧化磷酸化相关基因的表达降低。然而,某些途径(例如，DNA复制)和基因(例如，与早期和晚期相比，CHCHD2）在EHP中完全或更严重地失调。据我们所知,这项研究首次提供了对遗传性骨髓衰竭综合征中人类造血缺陷的胚胎发作的见解，并揭示了造血发育向EHP的关键阶段的细胞和分子异常。
