Slug deficiency enhances self-renewal of hematopoietic stem cells during hematopoietic regeneration.
Both extrinsic and intrinsic mechanisms tightly govern hematopoietic stem cell (HSC) decisions of self-renewal and differentiation. However, transcription factors that can selectively regulate HSC self-renewal division after stress remain to be identified. Slug is an evolutionarily conserved zinc-finger transcription factor that is highly expressed in primitive hematopoietic cells and is critical for the radioprotection of these key cells. We studied the effect of Slug in the regulation of HSCs in Slug-deficient mice under normal and stress conditions using serial functional assays. Here, we show that Slug deficiency does not disturb hematopoiesis or alter HSC homeostasis and differentiation in bone marrow but increases the numbers of primitive hematopoietic cells in the extramedullary spleen site. Deletion of Slug enhances HSC repopulating potential but not its homing and differentiation ability. Furthermore, Slug deficiency increases HSC proliferation and repopulating potential in vivo after myelosuppression and accelerates HSC expansion during in vitro culture. Therefore, we propose that Slug is essential for controlling the transition of HSCs from relative quiescence under steady-state condition to rapid proliferation under stress conditions. Our data suggest that inhibition of Slug in HSCs may present a novel strategy for accelerating hematopoietic recovery, thus providing therapeutic benefits for patients after clinical myelosuppressive treatment.
Sun
Yan
Y
Center of Biomedical Research Excellence (COBRE) in Stem Biology and Regenerative Medicine, Center for Molecular Medicine, Maine Medical Center Research Institute, Maine Medical Center, Scarborough, ME, USA.
Shao
Lijian
L
Bai
Hao
H
Wang
Zack Z
ZZ
Wu
Wen-Shu
WS
D000818:Animals; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D005472:Fluorouracil / Q000633:toxicity; D006410:Hematopoiesis / Q000502:physiology*; D006411:Hematopoiesis, Extramedullary / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012038:Regeneration / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D013312:Stress, Physiological; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D005472:Fluorouracil