mTOR Signaling as a Regulator of Hematopoietic Stem Cell Fate
- 14 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Stem Cell Reviews and Reports
- Vol. 17 (4), 1312-1322
- https://doi.org/10.1007/s12015-021-10131-z
Abstract
Blood is generated throughout life by continued proliferation and differentiation of hematopoietic progenitors, while at the top of the hierarchy, hematopoietic stem cells (HSCs) remain largely quiescent. This way HSCs avoid senescence and preserve their capacity to repopulate the hematopoietic system. But HSCs are not always quiescent, proliferating extensively in conditions such as those found in the fetal liver. Understanding the elusive mechanisms that regulate HSC fate would enable us to comprehend a crucial piece of HSC biology and pave the way for ex-vivo HSC expansion with clear clinical benefit. Here we review how metabolism, endoplasmic reticulum stress and oxidative stress condition impact HSCs decision to self-renew or differentiate and how these signals integrate into the mammalian target of rapamycin (mTOR) pathway. We argue that the bone marrow microenvironment continuously favors differentiation through the activation of the mTOR complex (mTORC)1 signaling, while the fetal liver microenvironment favors self-renewal through the inverse mechanism. In addition, we also postulate that strategies that have successfully achieved HSC expansion, directly or indirectly, lead to the inactivation of mTORC1. Finally, we propose a mechanism by which mTOR signaling, during cell division, conditions HSC fate. This mechanism has already been demonstrated in mature hematopoietic cells (T-cells), that face a similar decision after activation, either undergoing clonal expansion or differentiation. Graphical AbstractKeywords
Funding Information
- Fundação para a Ciência e a Tecnologia (Healthy Aging 2020-CENTRO-01-0145-FEDER-000012-N2323)
- Fundação para a Ciência e a Tecnologia (POCI-01-0145-FEDER-007440)
- Fundação para a Ciência e a Tecnologia (UIDB/04539/2020)
- National Institutes of Health (NIH 5P30AG028718)
This publication has 156 references indexed in Scilit:
- The Hallmarks of AgingCell, 2013
- Temporal Changes in PTEN and mTORC2 Regulation of Hematopoietic Stem Cell Self-Renewal and Leukemia SuppressionCell Stem Cell, 2012
- Asymmetric cancer cell division regulated by AKTProceedings of the National Academy of Sciences of the United States of America, 2011
- Cell-Type-Dependent Regulation of mTORC1 by REDD1 and the Tumor Suppressors TSC1/TSC2 and LKB1 in Response to HypoxiaMolecular and Cellular Biology, 2011
- Ex vivo rapamycin treatment of human cord blood CD34+ cells enhances their engraftment of NSG miceBlood Cells, Molecules, and Diseases, 2011
- mTOR Mediates Wnt-Induced Epidermal Stem Cell Exhaustion and AgingCell Stem Cell, 2009
- TSC–mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen speciesThe Journal of Experimental Medicine, 2008
- A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expressionAmerican Journal of Physiology-Cell Physiology, 2008
- Imaging Hematopoietic Precursor Division in Real TimeCell Stem Cell, 2007
- Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defectJCI Insight, 2006