Inflammatory signaling regulates embryonic hematopoietic stem and progenitor cell production.
Inflammatory signaling regulates embryonic hematopoietic stem and progenitor cell production.
复制标题
DOI：
10.1101/gad.253302.114
复制
发表时间：
2014-12-01
影响因子：
10.5
通讯作者：
Speck NA
中科院分区：
文献类型：
--
作者：
Li Y;Esain V;Teng L;Xu J;Kwan W;Frost IM;Yzaguirre AD;Cai X;Cortes M;Maijenburg MW;Tober J;Dzierzak E;Orkin SH;Tan K;North TE;Speck NA
在此，Li等人表明炎症信号传导调节胚胎造血干细胞和祖细胞（HSPC）形成。来自妊娠中期小鼠胚胎的主动脉/性腺/中肾（AGM）区域的HSC表达了强大的先天免疫/炎症特征。缺乏干扰素γ（IFN-γ）或IFN-α信号传导的小鼠胚胎以及缺乏IFN-γ和IFN-γ活性的斑马鱼的AGM HSPC较少。在人胎肝CD 34 + HSPC中鉴定的IRF 2占据基因在人和小鼠HSPC中转录活跃。鉴定调控胚胎中造血干细胞和祖细胞（HSPC）形成的信号传导途径将指导离体产生和扩增HSPC的努力。在这里，我们表明，无菌强直炎症信号调节胚胎HSPC的形成。具有淋巴潜能的祖细胞和来自妊娠中期小鼠胚胎的主动脉/性腺/中肾（AGM）区域的造血干细胞（HSC）的表达谱揭示了强大的先天免疫/炎症特征。缺乏干扰素γ（IFN-γ）或IFN-α信号传导的小鼠胚胎和缺乏IFN-γ和IFN-γ活性的斑马鱼吗啡突变体具有显著较少的AGM HSPC。相反，干扰素调节因子2（IRF 2），干扰素信号传导的负调节因子，敲低，增加干扰素靶基因的表达和斑马鱼HSPC的生产。染色质免疫沉淀（ChIP）结合测序（ChIP-seq）和表达分析表明，在人胎肝CD 34 + HSPC中鉴定的IRF 2占据基因在人和小鼠HSPC中活跃转录。此外，我们证明了原始骨髓细胞群有助于局部炎症反应，从而影响AGM区域HSPC产生的规模。因此，不育炎症信号传导是在胚胎发育期间调节HSPC产生的进化上保守的途径。
Here, Li et al. show that inflammatory signaling regulates embryonic hematopoietic stem and progenitor cell (HSPC) formation. HSCs from aorta/gonad/mesonephros (AGM) regions of midgestation mouse embryos expressed a robust innate immune/inflammatory signature. Mouse embryos lacking interferon γ (IFN-γ )or IFN-α signaling and zebrafish lacking IFN-γ and IFN-ϕ activity had fewer AGM HSPCs. IRF2-occupied genes identified in human fetal liver CD34+ HSPCs were actively transcribed in human and mouse HSPCs. Identifying signaling pathways that regulate hematopoietic stem and progenitor cell (HSPC) formation in the embryo will guide efforts to produce and expand HSPCs ex vivo. Here we show that sterile tonic inflammatory signaling regulates embryonic HSPC formation. Expression profiling of progenitors with lymphoid potential and hematopoietic stem cells (HSCs) from aorta/gonad/mesonephros (AGM) regions of midgestation mouse embryos revealed a robust innate immune/inflammatory signature. Mouse embryos lacking interferon γ (IFN-γ) or IFN-α signaling and zebrafish morphants lacking IFN-γ and IFN-ϕ activity had significantly fewer AGM HSPCs. Conversely, knockdown of IFN regulatory factor 2 (IRF2), a negative regulator of IFN signaling, increased expression of IFN target genes and HSPC production in zebrafish. Chromatin immunoprecipitation (ChIP) combined with sequencing (ChIP-seq) and expression analyses demonstrated that IRF2-occupied genes identified in human fetal liver CD34+ HSPCs are actively transcribed in human and mouse HSPCs. Furthermore, we demonstrate that the primitive myeloid population contributes to the local inflammatory response to impact the scale of HSPC production in the AGM region. Thus, sterile inflammatory signaling is an evolutionarily conserved pathway regulating the production of HSPCs during embryonic development.