A complex interplay between PGC-1 co-activators and mTORC1 regulates hematopoietic recovery following 5-fluorouracil treatment.
In vitro stimulation of HSCs with growth factors generally leads to their depletion. Understanding the molecular mechanisms underlying expansion of HSCs in vivo following myeloablation could lead to successful expansion of HSCs ex vivo for therapeutic purposes. Current findings show that mTORC1 is activated in HSPCs following 5-fluorouracil treatment and that mTORC1 activation is dependent on mitochondrial ETC capacity of HSPCs. Moreover, expression of PGC-1 family members, proteins that regulate mitochondrial biogenesis, in HSPCs following 5-fluorouracil treatment changes; also, these proteins play a stage specific role in hematopoietic recovery. While PRC regulates HSCs' expansion during early recovery phase, PGC-1α regulates progenitor cell proliferation and recovery of hematopoiesis during later phase. During early recovery phase, PRC expression, mitochondrial activity and mTORC1 activation are relatively higher in PGC-1α(-/-) HSCs compared to WT HSCs, and PGC-1α(-/-) HSCs show greater expansion. Administration of rapamycin, but not NAC, during early recovery phase improves WT HSC numbers but decreases PGC-1α(-/-) HSC numbers. The current findings demonstrate that mTOR activation can increase HSC numbers provided that the energy demand created by mTOR activation is successfully met. Thus, critical tuning between mTORC1 activation and mitochondrial ETC capacity is crucial for HSC maintenance/expansion in response to mitogenic stimulation.
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, USA. Electronic address: sbasu86@gmail.com.
Sunanda
S
Basu
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; C469992:Ddit4 protein, mouse; D046912:Multiprotein Complexes; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D005472:Fluorouracil; D020123:Sirolimus
ETC; HSC; HSPC; N-acetyl cysteine; NAC; PGC-1 related coactivator; PGC-1α; PRC; electron transport chain; hematopoietic stem and progenitor cell; hematopoietic stem cell; mTORC1; mammalian target of rapamycin complex1; peroxisome proliferator-activated receptor gamma co-activator-1α