The development and maintenance of hematopoietic stem/progenitor cells and microglia in zebrafish

Abstract

Hematopoietic stem and progenitor cells (HSPCs) are capable of self-renewal and continuously replenishing all mature blood lineages throughout life. The proper preservation of HSPCs is indispensable for the normal function of various tissue and organs. However, the molecular signaling regulation underlying the maintenance and expansion remains not fully understood. Here, in the first part, we show a surprising role of Csf1rb, a zebrafish homologue of mammalian CSF1R, a primary regulator for myeloid lineage development, in preserving the HSPCs pool via maintaining the proliferation of HSPCs. The deficiency of csf1rb leads to reduction of both HSPCs and their differentiated progenies including myeloid, lymphoid and erythroid. Interestingly, loss-of-function and gain-of-function assays demonstrate that none of the canonical ligands for CSF1R in zebrafish, including Csf1a, Csf1b, and Il34 serves as the ligand of Csf1rb. Thus, our data indicate a previously unappreciated role of CSF1R in maintaining the expansion of HSPCs, which is independent of known ligands. In the second part, we focus on the mechanisms underlying the maintenance of microglia, which serve as immune surveillant cells in the central nervous system, and are essential in regulating neuronal development and activity. In zebrafish, microglia originate from both rostral blood island (RBI) and ventral wall of aorta (VDA) derived hematopoiesis. Embryonic microglia which are purely RBI-origins will be gradually replaced by VDA-originated microglia over time. However, the mechanisms underlying the differential maintenance of two waves of microglia remain unknown. Here, we demonstrate that VDA-originated microglia are more actively dividing and possess lower expression levels of mafbb & mafba, the orthologues of cell cycle suppressor gene Mafb in mouse macrophages. The ectopic expression of mafbb in VDA-originated microglia reduces their contribution to total microglia. These data suggest the negative regulation of Mafbb in microglia maintenance, which is worthy of further investigation

Date of Award	2019
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology