Cooperative Transcription Factor Induction Mediates Hemogenic Reprogramming
Cooperative Transcription Factor Induction Mediates Hemogenic Reprogramming
复制标题
DOI：
10.1016/j.celrep.2018.11.032
复制
发表时间：
2018-12-04
期刊：
影响因子：
8.8
通讯作者：
Pereira, Carlos-Filipe
中科院分区：
文献类型：
--
作者：
Gomes, Andreia M.;Kurochkin, Ilia;Pereira, Carlos-Filipe
在发育过程中，造血干细胞和祖细胞（HSPC）通过称为内皮向造血转化（EHT）的过程从特化内皮细胞产生。驱动人类HSPC出现的遗传程序在很大程度上仍然未知。我们以前报道过，小鼠成纤维细胞的造血前体细胞的产生重演了发育性造血。在这里，我们证明，人成纤维细胞可以通过相同的转录因子重编程为生血细胞。诱导的细胞显示动态EHT转录程序，产生造血后代，具有HSPC细胞表面表型，并重新填充免疫缺陷小鼠3个月。在机制上，GATA 2和GFI1B相互作用并共同占据一组靶标。这种协同结合通过开放增强子和启动子的接合、启动成纤维细胞基因的沉默和激活生血程序来反映。然而，GATA 2在重编程的早期阶段显示出主导和独立的靶向活性。这些发现揭示了控制人类HSC特化的过程，并支持产生用于临床应用的重编程HSC。
During development, hematopoietic stem and progenitor cells (HSPCs) arise from specialized endothelial cells by a process termed endothelial-to-hematopoietic transition (EHT). The genetic program driving human HSPC emergence remains largely unknown. We previously reported that the generation of hemogenic precursor cells from mouse fibroblasts recapitulates developmental hematopoiesis. Here, we demonstrate that human fibroblasts can be reprogrammed into hemogenic cells by the same transcription factors. Induced cells display dynamic EHT transcriptional programs, generate hematopoietic progeny, possess HSPC cell surface phenotype, and repopulate immunodeficient mice for 3 months. Mechanistically, GATA2 and GFI1B interact and co-occupy a cohort of targets. This cooperative binding is reflected by engagement of open enhancers and promoters, initiating silencing of fibroblast genes and activating the hemogenic program. However, GATA2 displays dominant and independent targeting activity during the early phases of reprogramming. These findings shed light on the processes controlling human HSC specification and support generation of reprogrammed HSCs for clinical applications.