LepR+ niche cell-derived AREG compromises hematopoietic stem cell maintenance under conditions of DNA repair deficiency and aging.
Limei WuQiqi LinSrinivas ChatlaSurya Prakash AmarachinthaAndrew F WilsonNeha AtaleZhenxia J GaoJonathan JosephEmily WolffWei DuPublished in: Blood (2023)
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.
Keyphrases
- dna repair
- dna damage
- bone marrow
- induced apoptosis
- hematopoietic stem cell
- high fat diet induced
- dna damage response
- oxidative stress
- cell cycle arrest
- stem cells
- wild type
- dendritic cells
- acute myeloid leukemia
- genome wide
- endoplasmic reticulum stress
- type diabetes
- cell death
- mesenchymal stem cells
- gene expression
- copy number
- insulin resistance
- dna methylation
- skeletal muscle
- replacement therapy
- genome wide identification
- signaling pathway
- smoking cessation