mTOR Signaling as a Regulator of Hematopoietic Stem Cell Fate

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 Abstract

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Data Availability

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Funding

The authors would like to acknowledge funding from UIDB/04539/2020, Healthy Aging 2020-CENTRO-01-0145-FEDER-000012-N2323, POCI-01-0145-FEDER-007440, and the NIH 5P30 AG028718.

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Hélia Fernandes and João Moura conceived and wrote the manuscript, Eugénia Carvalho critically reviewed and discussed the manuscript. All authors approved the final version of this manuscript.

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Correspondence to João Moura.

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Highlights

• The mTOR pathway integrates metabolic, oxidative and endoplasmic reticulum stress and other environmental signals that condition HSC fate.

• Bone marrow microenvironment suppresses HSC expansion through mTOR signaling, protecting HSC from exhaustion.

• Many strategies leading to ex vivo HSC expansion indirectly suppress mTOR signaling.

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Fernandes, H., Moura, J. & Carvalho, E. mTOR Signaling as a Regulator of Hematopoietic Stem Cell Fate. Stem Cell Rev and Rep (2021). https://doi.org/10.1007/s12015-021-10131-z

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Keywords

  • Hematopoietic stem cell
  • Bone marrow microenvironment
  • HSC expansion
  • mTOR
  • Fate decision mechanism