Article ; Online: A complex interplay between PGC-1 co-activators and mTORC1 regulates hematopoietic recovery following 5-fluorouracil treatment.
Stem cell research
2014 Volume 12, Issue 1, Page(s) 178–193
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Animals ; Antimetabolites, Antineoplastic/pharmacology ; Cell Proliferation/drug effects ; Fluorouracil/pharmacology ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism ; Multiprotein Complexes/metabolism ; Reactive Oxygen Species/metabolism ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/metabolism ; Transcription Factors/deficiency ; Transcription Factors/genetics ; Transcription Factors/metabolism |
| Chemical Substances | Antimetabolites, Antineoplastic ; Ddit4 protein, mouse ; Multiprotein Complexes ; Reactive Oxygen Species ; Transcription Factors ; peroxisome-proliferator-activated receptor-gamma coactivator-1 ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Fluorouracil (U3P01618RT) ; Sirolimus (W36ZG6FT64) |
| Language | English |
| Publishing date | 2014-01 |
| Publishing country | England |
| Document type | Journal Article |
| ISSN | 1876-7753 |
| ISSN (online) | 1876-7753 |
| DOI | 10.1016/j.scr.2013.10.006 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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