PEAR1 is a potential regulator of early hematopoiesis of human pluripotent stem cells
PEAR1 is a potential regulator of early hematopoiesis of human pluripotent stem cells
复制标题
DOI：
10.1002/jcp.30924
复制
发表时间：
2022-11
影响因子：
5.6
通讯作者：
Shuo Zhang;Kengyuan Qu;Shuzhen Lyu;Dixie L. Hoyle;Cory J. Smith;Linzhao Cheng;Tao Cheng;Jun Shen;Zack Z Wang
中科院分区：
文献类型：
--
作者：
Shuo Zhang;Kengyuan Qu;Shuzhen Lyu;Dixie L. Hoyle;Cory J. Smith;Linzhao Cheng;Tao Cheng;Jun Shen;Zack Z Wang
生血内皮细胞（Hemogenic endothelial cell，HE）是在造血发育过程中产生造血干/祖细胞的特化内皮细胞。调节人HE细胞内皮向造血转化（EHT）的潜在机制尚未完全了解。在这里，我们确定了血小板内皮聚集受体-1（PEAR 1）作为人类多能干细胞（hPSC）早期造血发育的新型调节因子。我们发现PEAP 1的表达在造血发育过程中升高。PEAR 1+细胞亚群与CD 34 + CD 144 + CD 184 + CD 73 −动脉型HE细胞重叠。通过RNA测序进行的转录组分析表明，TAL 1/SCL、GATA 2、MYB、RUNX 1和其他造血发育的关键转录因子主要在PEAR 1+细胞中表达，而编码小生境相关信号的基因，如纤连蛋白、玻连蛋白、骨形态发生蛋白和jagged 1，在PEAR 1 −细胞中高度表达。与PEAR 1 −细胞相比，分离的PEAR 1+细胞在内皮小生境上表现出显著更大的EHT能力。集落形成单位（CFU）测定证明PEAR 1+衍生的造血细胞的多谱系造血潜能。此外，通过CRISPR/Cas9技术在hPSC中敲除PEAR 1揭示了造血分化受损，导致EHT能力降低，造血相关转录因子表达降低，以及小生境相关信号表达增加。总之，这项研究揭示了PEAR 1在平衡早期造血命运决定的内在和外在信号中的新作用。
Hemogenic endothelial (HE) cells are specialized endothelial cells to give rise to hematopoietic stem/progenitor cells during hematopoietic development. The underlying mechanisms that regulate endothelial‐to‐hematopoietic transition (EHT) of human HE cells are not fully understand. Here, we identified platelet endothelial aggregation receptor‐1 (PEAR1) as a novel regulator of early hematopoietic development in human pluripotent stem cells (hPSCs). We found that the expression of PEAP1 was elevated during hematopoietic development. A subpopulation of PEAR1+ cells overlapped with CD34+CD144+CD184+CD73− arterial‐type HE cells. Transcriptome analysis by RNA sequencing indicated that TAL1/SCL, GATA2, MYB, RUNX1 and other key transcription factors for hematopoietic development were mainly expressed in PEAR1+ cells, whereas the genes encoding for niche‐related signals, such as fibronectin, vitronectin, bone morphogenetic proteins and jagged1, were highly expressed in PEAR1− cells. The isolated PEAR1+ cells exhibited significantly greater EHT capacity on endothelial niche, compared with the PEAR1− cells. Colony‐forming unit (CFU) assays demonstrated the multilineage hematopoietic potential of PEAR1+‐derived hematopoietic cells. Furthermore, PEAR1 knockout in hPSCs by CRISPR/Cas9 technology revealed that the hematopoietic differentiation was impaired, resulting in decreased EHT capacity, decreased expression of hematopoietic‐related transcription factors, and increased expression of niche‐related signals. In summary, this study revealed a novel role of PEAR1 in balancing intrinsic and extrinsic signals for early hematopoietic fate decision.