Aberrant early hematopoietic progenitor formation marks the onset of hematopoietic defects in Shwachman–Diamond syndrome

IF 2.3 3区 医学 Q2 HEMATOLOGY
Alejandra Lagos-Monzon, Stephanie Ng, Alice M. Luca, Hongbing Li, Mathura Sabanayagam, Mariana Benicio, Houtan Moshiri, Richard Armstrong, Chetan Tailor, Marion Kennedy, Eyal Grunebaum, Gordon Keller, Yigal Dror
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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.

Abstract Image

异常的早期造血祖细胞形成标志着 Shwachman-Diamond 综合征造血缺陷的开始。
舒瓦赫曼-钻石综合征(SDS)是一种遗传性骨髓衰竭疾病,通常在婴儿期发病。在揭示 SDS 的致病突变基因(SBDS 及其他)、核糖体缺陷和造血畸变方面取得了进展。然而,造血功能衰竭的机制仍然不明,治疗方案也很有限。在此,我们研究了 SDS 胚胎造血损伤的发病机制。我们生成了 SDS 和对照组人源诱导多能干细胞(iPSCs)。SDS iPSCs重现了SDS的血液表型。对确定性造血的详细逐步评估显示,缺陷始于中胚层和造血内皮正常诱导后的早期造血祖细胞(EHP)阶段。EHP 的造血潜能明显降低,而在 SDS iPSCs 中引入 SBDS 可改善集落形成。转录组分析显示,在未分化和已分化的 iPSCs 中,核糖体和氧化磷酸化相关基因的表达减少。然而,与早期和晚期相比,某些途径(如 DNA 复制)和基因(如 CHCHD2)在 EHPs 中完全或更严重地失调。据我们所知,这项研究首次揭示了遗传性骨髓衰竭综合征中人类造血缺陷的胚胎发病过程,并揭示了EHPs造血发育关键阶段的细胞和分子畸变。
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来源期刊
CiteScore
5.50
自引率
0.00%
发文量
168
审稿时长
4-8 weeks
期刊介绍: European Journal of Haematology is an international journal for communication of basic and clinical research in haematology. The journal welcomes manuscripts on molecular, cellular and clinical research on diseases of the blood, vascular and lymphatic tissue, and on basic molecular and cellular research related to normal development and function of the blood, vascular and lymphatic tissue. The journal also welcomes reviews on clinical haematology and basic research, case reports, and clinical pictures.
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