LepR+ niche cell-derived AREG compromises hematopoietic stem cell maintenance under conditions of DNA repair deficiency and aging.

The crosstalk between extrinsic niche-derived and intrinsic hematopoietic stem cell (HSC) factors controlling HSC maintenance remain elusive. Here we demonstrate that amphiregulin (AREG) from bone marrow (BM) leptin receptor (LepR+) niche cells is an important factor that mediates the crosstalk between BM niche and HSCs in stem cell maintenance. Mice deficient for the DNA repair gene Brca2 specifically in LepR+ cells (LepR-Cre;Brca2fl/fl) exhibit increased frequencies of total and myeloid-biased HSCs. Furthermore, HSCs from LepR-Cre;Brca2fl/fl mice show compromised repopulation, increased expansion of donor-derived myeloid-biased HSCs and myeloid output. Brca2-deficient BM LepR+ cells exhibit persistent DNA damage-inducible overproduction of AREG. Ex vivo treatment of WT HSCs, or systemic treatment of C57BL/6 mice, with recombinant AREG impairs repopulation, leading to HSC exhaustion. Conversely, inhibition of AREG by anti-AREG neutralizing antibody or deletion of the Areg gene in LepR-Cre;Brca2fl/fl mice rescues the HSC defects caused by AREG. Mechanistically, AREG activates the PI3K/AKT/mTOR pathway, promotes HSC cycling and compromises HSC quiescence. Finally, we demonstrate that BM LepR+ niche cells from other DNA repair-deficient and aged mice also show persistent DNA damage-associated overexpression of AREG, which exerts similar negative effects on HSC maintenance. We have therefore identified an important factor regulating HSCs function under conditions of DNA repair deficiency and aging.