Abstract
Macrophage colony-stimulating factor receptor (M-CSFR/CSF1R) signaling is crucial for the differentiation, proliferation, and survival of myeloid cells. The CSF1R pathway is a promising therapeutic target in many human diseases, including neurological disorders and cancer. Zebrafish are commonly used for human disease modeling and preclinical therapeutic screening. Therefore, it is necessary to understand the proper function of cytokine signaling in zebrafish to reliably model human-related diseases. Here, we investigate the roles of zebrafish Csf1rs and their ligands (Csf1a, Csf1b, and Il34) in embryonic and adult myelopoiesis. The proliferative effect of exogenous Csf1a on embryonic macrophages is connected to both receptors, Csf1ra and Csf1rb, however there is no evident effect of Csf1b in zebrafish embryonic myelopoiesis. Furthermore, we uncover an unknown role of Csf1rb in zebrafish granulopoiesis. Deregulation of Csf1rb signaling leads to failure in myeloid differentiation, resulting in neutropenia throughout the whole lifespan. Surprisingly, Il34 signaling through Csf1rb seems to be of high importance as both csf1rb D4bp-deficient and il34 D5bp-deficient zebrafish larvae lack granulocytes. Our single-cell RNA sequencing analysis of adult whole kidney marrow (WKM) hematopoietic cells suggests that csf1rb is expressed mainly by blood and myeloid progenitors, and the expression of csf1ra and csf1rb is nonoverlapping. We point out differentially expressed genes important in hematopoietic cell differentiation and immune response in selected WKM populations. Our findings could improve the understanding of myeloid cell function and lead to the further study of CSF1R pathway deregulation in disease, mostly in cancerogenesis.
| Original language | English |
|---|---|
| Pages (from-to) | 1474-1488 |
| Number of pages | 15 |
| Journal | Blood Advances |
| Volume | 6 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 8 Mar 2022 |
Bibliographical note
Funding Information:This work was supported by the Czech Science Foundation (18-18363S), LM2018130, and 68378050-KAV-NPUI to P.B. and by the ERC Advanced Grant “DanioPattern” (694289) to C.N.-V. and U.I.
Funding Information:
The authors thank Nikol Pavlu, Tereza Hojerova, and Tereza Hin-garova for animal care. They also thank Trevor Epp for editing the manuscript and Leonard Zon for providing mpeg1:EGFP and mpx:EGFP reporter fish lines. The authors acknowledge Michal Kolar for help with sc-RNA-transcriptomics (LM2018131) and the Light Microscopy Core Facility, IMG CAS, Prague, Czech Republic, supported by MEYS (LM2018129, CZ.02.1.01/0.0/0.0/ 18_046/0016045) for their support with the confocal imaging.
Publisher Copyright:
© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
