Differentiation of fetal hematopoietic stem cells requires ARID4B to restrict autocrine KITLG/KIT-Src signaling

• DOI: 10.1016/j.celrep.2021.110036
• Publication Date: 2021-11-23T15:34:39Z
• Authors: In-Chi Young; Bogang Wu; Jaclyn Andricovich; Sung-Ting Chuang; Rong Li; Alexandros Tzatsos; Ray-Chang Wu; Mei-Yi Wu
• Keywords: Male; Mice, Knockout; Stem Cell Factor; 0303 health sciences; Cell Differentiation; Hematopoietic Stem Cells; Article; Hematopoiesis; DNA-Binding Proteins; Mice, Inbred C57BL; Autocrine Communication; Mice; Proto-Oncogene Proteins c-kit; 03 medical and health sciences; src-Family Kinases; Animals; Female; Cell Self Renewal; Stem Cell Niche; Cell Proliferation; Signal Transduction; Transcription Factors

Balance between the hematopoietic stem cell (HSC) duality to either possess self-renewal capacity or differentiate into multipotency progenitors (MPPs) is crucial for maintaining homeostasis of the hematopoietic stem/progenitor cell (HSPC) compartment. To retain the HSC self-renewal activity, KIT, a receptor tyrosine kinase, in HSCs is activated by its cognate ligand KITLG originating from niche cells. Here, we show that AT-rich interaction domain 4B (ARID4B) interferes with KITLG/KIT signaling, consequently allowing HSC differentiation. Conditional Arid4b knockout in mouse hematopoietic cells blocks fetal HSC differentiation, preventing hematopoiesis. Mechanistically, ARID4B-deficient HSCs self-express KITLG and overexpress KIT. As to downstream pathways of KITLG/KIT signaling, inhibition of Src family kinases rescues the HSC differentiation defect elicited by ARID4B loss. In summary, the intrinsic ARID4B-KITLG/KIT-Src axis is an HSPC regulatory program that enables the differentiation state, while KIT stimulation by KITLG from niche cells preserves the HSPC undifferentiated pool.