Abstract
Erythroblastic islands are a specialized niche that contain a central macrophage surrounded by erythroid cells at various stages of maturation. However, identifying the precise genetic and transcriptional control mechanisms in the island macrophage remains difficult due to macrophage heterogeneity. Using unbiased global sequencing and directed genetic approaches focused on early mammalian development, we find that fetal liver macrophages exhibit a unique expression signature that differentiates them from erythroid and adult macrophage cells. The importance of erythroid Krüppel-like factor (EKLF)/KLF1 in this identity is shown by expression analyses in EKLF-/- and in EKLF-marked macrophage cells. Single-cell sequence analysis simplifies heterogeneity and identifies clusters of genes important for EKLF-dependent macrophage function and novel cell surface biomarkers. Remarkably, this singular set of macrophage island cells appears transiently during embryogenesis. Together, these studies provide a detailed perspective on the importance of EKLF in the establishment of the dynamic gene expression network within erythroblastic islands in the developing embryo and provide the means for their efficient isolation.
Highlights
Maturation of red blood cells in vivo occurs within specialized niches called ‘erythroblastic islands’ that consist of a central macrophage surrounded by erythroid cells at various stages of differentiation (Chasis and Mohandas, 2008; Hom et al, 2015; Klei et al, 2017; Manwani and Bieker, 2008; Yeo et al, 2019)
When we analyze the functional categories of genes significantly enriched in each of the subsets (Figure 4—figure supplement 1B), we find that the erythroid Kruppel-like factor (EKLF)/green fluorescent protein (GFP)+F4/80+ subset is enriched for genes involved in heme synthesis, iron transport and homeostasis, and myeloid/erythroid differentiation (Table 2), functions consistent with those performed by erythroblast island macrophages
There is overlap among the cell populations, we have shown that E13.5 murine fetal liver (FL) F4/80+ macrophages exhibit a distinct expression pattern when compared to adult spleen F4/80+ macrophage, one that is divergent from that of FL erythroid cells, providing them with a discrete cellular identity
Summary
Maturation of red blood cells in vivo occurs within specialized niches called ‘erythroblastic islands’ that consist of a central macrophage surrounded by erythroid cells at various stages of differentiation (Chasis and Mohandas, 2008; Hom et al, 2015; Klei et al, 2017; Manwani and Bieker, 2008; Yeo et al, 2019). Studies suggest that even an 80% decrease in mouse resident macrophage levels still enables a normal recovery from stress (Ulyanova et al, 2016), this response is effectively aided by Mukherjee et al eLife 2021;10:e61070.
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