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XPR1 regulates fetal liver macrophage development, identity, and pyrenocyte clearance
Sebastian A Stifter1, Mitchell Bijnen1, Selma Tuzlak1
1Institute of Experimental Immunology, University of Zurich , Zurich, Switzerland.
Insights
The phosphate exporter XPR1 is essential for fetal macrophage development and function. Loss of XPR1 impairs the clearance of erythroblast nuclei, impacting erythropoiesis.
Area of Science:
- Cell Biology
- Developmental Biology
- Immunology
Background:
- Inorganic phosphate (Pi) is vital for cellular processes, including nucleic acid synthesis and bone growth.
- Pi transporters are critical, with mutations causing lethality.
- The phosphate exporter XPR1's role in development is largely unknown.
Purpose of the Study:
- To investigate the role of the phosphate exporter XPR1 in macrophage development and function.
- To determine the impact of XPR1 deficiency on fetal and adult hematopoiesis.
Main Methods:
- Single-cell RNA-seq and flow cytometry in conditional Xpr1-deficient mice.
- Analysis of hematopoietic and CD206+ cell populations.
- Assessment of erythroblast nuclear clearance and macrophage populations.
Main Results:
- XPR1 deficiency resulted in the loss of Kupffer cell transcriptional programs in fetal liver macrophages.
- A developmental shift towards interferon-activated monocyte/macrophage states was observed.
- Embryonic XPR1 loss caused impaired clearance of erythroblast nuclei.
- Adult XPR1 deficiency reduced splenic red pulp and bone marrow macrophages.
Conclusions:
- XPR1 is crucial for the development and identity of fetal liver macrophages.
- XPR1 plays a significant role in the function of macrophages involved in erythropoiesis.
- XPR1 is required for efficient nuclear clearance during red blood cell development.
Abstract:
Inorganic phosphate (Pi) is an essential nutrient for all organisms. It has critical functions in lipid and nucleic acid synthesis, protein signaling and bone growth. Loss-of-function mutations in Pi transporters lead to embryonic and neonatal lethality. Here, we show that the only known Pi exporter, XPR1, is critical for the development of fetal macrophages in the liver and the spleen. Single-cell RNA-seq and flow cytometry analyses in conditional mice lacking Xpr1 in hematopoietic and/or CD206+ cells revealed loss of the Kupffer cell transcriptional program and a shift in the development of fetal liver monocytes towards an interferon-activated monocyte/macrophage state. Functionally, Xpr1 deficiency in embryos led to a failure to clear nuclei expelled from erythroblasts. In adulthood, splenic red pulp and bone marrow macrophages were also reduced upon loss of intrinsic Xpr1. Collectively, these findings reveal that XPR1 is required for the development, identity, and function of macrophages involved in erythropoiesis.
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