Abstract
The first adult repopulating hematopoietic stem cells (HSCs) are found in the aorta-gonad-mesonephros (AGM) region, which are produced from hemogenic endothelial cells. Embryonic head is the other site for HSC development. Wild-type p53-induced phosphatase 1 (Wip1) is a type-2Cδ family serine/threonine phosphatase involved in various cellular processes such as lymphoid development and differentiation of adult HSCs. Most recently, we have shown that Wip1 modulates the pre-HSC maturation in the AGM region. However, it is not clear whether Wip1 regulates hematopoiesis in the embryonic head. Here we reported that disruption of Wip1 resulted in a decrease of hematopoietic progenitor cell number in the embryonic head. In vivo transplantation assays showed a reduction of HSC function after Wip1 ablation. We established that Wip1 deletion reduced the frequency and cell number of microglia in the embryonic head. Further observations revealed that Wip1 absence enhanced the gene expression of microglia-derived pro-inflammatory factors. Thus, it is likely that Wip1 functions as a positive regulator in HSC development by regulating the function of microglia in the embryonic head.
Highlights
Hematopoietic stem cells (HSCs) provide hematopoietic progenitor cells (HPCs) and mature blood cells depending on the capacity of self-renewing and differentiation
To test the hematopoietic progenitor function, colony-forming unit-culture (CFU-C) assays confirmed a dramatic decrease in HPC function from E9.5 to E11.5 Wild-type p53-induced phosphatase 1 (Wip1)−/− head compared to WT head, including the reductions of burst forming unit-erythroid (BFUE) of E11.5 (5 ± 5 vs. 80 ± 42), CFU-granulocyte-macrophage (CFU-GM) in E9.5–E11.5 (E9.5, 0 ± 0 vs. 7 ± 2; E10.5, 238 ± 81 vs. 486 ± 80; E11.5, 365 ± 50 vs. 993 ± 165), and CFU-granulocyte-erythroid-macrophage-megakaryocyte [CFUGEMM(Mix)] in E9.5 (0 ± 0 vs. 1 ± 1) and E11.5 (10 ± 10 vs. 120 ± 61) (Figure 1F), which is similar to the trend of CD41-enriched HPCs in the embryonic head (Figure 1E) and AGM region (He et al, 2021)
These results suggest that Wip1 is involved in HPC development of the embryonic head
Summary
Hematopoietic stem cells (HSCs) provide hematopoietic progenitor cells (HPCs) and mature blood cells depending on the capacity of self-renewing and differentiation. The aorta-gonad-mesonephros (AGM) region is the site for the generation of the first HSC with long-term repopulating potential in the embryo (Muller et al, 1994). Previous studies have identified the regulatory molecules of AGM HSC productions, such as pro-inflammatory factors, adrenomedullin (ADM)/receptor activity-modifying protein 2 (RAMP2), and G protein-coupled receptor 56 (Gpr56) (Li et al, 2014, 2019; Solaimani Kartalaei et al, 2015; Dzierzak and Bigas, 2018; Mariani et al, 2019; Yvernogeau et al, 2020). Definitive erythro-myeloid progenitors (EMPs) are emerged from ECs in the yolk sac beginning at embryonic day (E) 8/8.5.
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