Crowley Stephanie J, Yang Wei, White Lynn S, Wu Jun, Li Yanan, Schmidt Haley, Choi Kyunghee, Magee Jeffrey A, Bednarski Jeffrey J
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
Department of Genetics, Washington University School of Medicine, St. Louis, MO.
Blood Adv. 2025 Aug 12;9(15):4043-4057. doi: 10.1182/bloodadvances.2024014916.
Hematopoietic stem cells (HSCs) rapidly expand during fetal development and after stress. Here, we identify B-cell lymphoma-2-associated factor 1 (BCLAF1) as a regulator of HSC repopulation activity, with roles in the expansion of fetal HSCs and hematopoietic reconstitution after stem cell transplantation. Using mice with hematopoietic-specific and inducible deletion of Bclaf1, we find that BCLAF1 promotes fetal HSC development but is dispensable for the maintenance of adult HSCs at steady state. Loss of BCLAF1 in either fetal or adult HSCs significantly impairs their self-renewal and multilineage reconstitution activity after stem cell transplantation. Single-cell RNA sequencing of fetal hematopoietic progenitors reveals that loss of BCLAF1 reduces long-term HSCs and restrains the expression of stress response genes. BCLAF1 associates with chromatin throughout the genome of fetal and adult hematopoietic cells, likely through indirect mechanisms, to regulate transcriptional programs. These results establish a novel function for the transcriptional regulator BCLAF1 in limiting stress responses in HSCs, thereby preserving HSC development during embryogenesis and repopulation function after stem cell transplant.
造血干细胞（HSCs）在胎儿发育期间和应激后会迅速扩增。在此，我们确定B细胞淋巴瘤-2相关因子1（BCLAF1）是HSC再增殖活性的调节因子，在胎儿HSCs的扩增以及干细胞移植后的造血重建中发挥作用。利用造血特异性且可诱导缺失Bclaf1的小鼠，我们发现BCLAF1促进胎儿HSC发育，但对于稳态下成年HSCs的维持并非必需。胎儿或成年HSCs中BCLAF1的缺失显著损害其在干细胞移植后的自我更新和多谱系重建活性。对胎儿造血祖细胞进行单细胞RNA测序发现，BCLAF1的缺失会减少长期HSCs并抑制应激反应基因的表达。BCLAF1可能通过间接机制与胎儿和成年造血细胞基因组中的染色质结合，以调节转录程序。这些结果确立了转录调节因子BCLAF1在限制HSCs应激反应中的新功能，从而在胚胎发育过程中维持HSC发育，并在干细胞移植后保持再增殖功能。
