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Hepatic Leukemia Factor Maintains Quiescence of Hematopoietic Stem Cells and Protects the Stem Cell Pool during Regeneration

Komorowska, Karolina LU ; Doyle, Alexander LU ; Wahlestedt, Martin LU ; Subramaniam, Agatheeswaran LU ; Debnath, Shubhranshu LU ; Chen, Jun LU ; Soneji, Shamit LU ; Van Handel, Ben; Mikkola, Hanna K.A. and Miharada, Kenichi LU , et al. (2017) In Cell Reports 21(12). p.3514-3523
Abstract

The transcription factor hepatic leukemia factor (HLF) is strongly expressed in hematopoietic stem cells (HSCs) and is thought to influence both HSC self-renewal and leukemogenesis. However, the physiological role of HLF in hematopoiesis and HSC function is unclear. Here, we report that mice lacking Hlf are viable with essentially normal hematopoietic parameters, including an intact HSC pool during steady-state hematopoiesis. In contrast, when challenged through transplantation, Hlf-deficient HSCs showed an impaired ability to reconstitute hematopoiesis and became gradually exhausted upon serial transplantation. Transcriptional profiling of Hlf-deficient HSCs revealed changes associated with enhanced cellular activation, and cell-cycle... (More)

The transcription factor hepatic leukemia factor (HLF) is strongly expressed in hematopoietic stem cells (HSCs) and is thought to influence both HSC self-renewal and leukemogenesis. However, the physiological role of HLF in hematopoiesis and HSC function is unclear. Here, we report that mice lacking Hlf are viable with essentially normal hematopoietic parameters, including an intact HSC pool during steady-state hematopoiesis. In contrast, when challenged through transplantation, Hlf-deficient HSCs showed an impaired ability to reconstitute hematopoiesis and became gradually exhausted upon serial transplantation. Transcriptional profiling of Hlf-deficient HSCs revealed changes associated with enhanced cellular activation, and cell-cycle analysis demonstrated a significant reduction of quiescent HSCs. Accordingly, toxic insults targeting dividing cells completely eradicated the HSC pool in Hlf-deficient mice. In summary, our findings point to HLF as a critical regulator of HSC quiescence and as an essential factor for maintaining the HSC pool during regeneration. Komorowska et al. report that the transcription factor HLF is required to maintain hematopoietic stem cell (HSC) function during regeneration. Moreover, Hlf-deficient HSCs are less quiescent. In accordance with this, toxic insults targeting dividing cells completely eradicate the HSC pool in Hlf-deficient mice.

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@article{30fe5051-eb1b-4035-8a9c-b119a145fd7b,
  abstract     = {<p>The transcription factor hepatic leukemia factor (HLF) is strongly expressed in hematopoietic stem cells (HSCs) and is thought to influence both HSC self-renewal and leukemogenesis. However, the physiological role of HLF in hematopoiesis and HSC function is unclear. Here, we report that mice lacking Hlf are viable with essentially normal hematopoietic parameters, including an intact HSC pool during steady-state hematopoiesis. In contrast, when challenged through transplantation, Hlf-deficient HSCs showed an impaired ability to reconstitute hematopoiesis and became gradually exhausted upon serial transplantation. Transcriptional profiling of Hlf-deficient HSCs revealed changes associated with enhanced cellular activation, and cell-cycle analysis demonstrated a significant reduction of quiescent HSCs. Accordingly, toxic insults targeting dividing cells completely eradicated the HSC pool in Hlf-deficient mice. In summary, our findings point to HLF as a critical regulator of HSC quiescence and as an essential factor for maintaining the HSC pool during regeneration. Komorowska et al. report that the transcription factor HLF is required to maintain hematopoietic stem cell (HSC) function during regeneration. Moreover, Hlf-deficient HSCs are less quiescent. In accordance with this, toxic insults targeting dividing cells completely eradicate the HSC pool in Hlf-deficient mice.</p>},
  author       = {Komorowska, Karolina and Doyle, Alexander and Wahlestedt, Martin and Subramaniam, Agatheeswaran and Debnath, Shubhranshu and Chen, Jun and Soneji, Shamit and Van Handel, Ben and Mikkola, Hanna K.A. and Miharada, Kenichi and Bryder, David and Larsson, Jonas and Magnusson, Mattias},
  issn         = {2211-1247},
  keyword      = {5FU,cell cycle,HLF,HSC,quiescence,reconstitution,self-renewal,stress,transcription factor,transplantation},
  language     = {eng},
  month        = {12},
  number       = {12},
  pages        = {3514--3523},
  publisher    = {Cell Press},
  series       = {Cell Reports},
  title        = {Hepatic Leukemia Factor Maintains Quiescence of Hematopoietic Stem Cells and Protects the Stem Cell Pool during Regeneration},
  url          = {http://dx.doi.org/10.1016/j.celrep.2017.11.084},
  volume       = {21},
  year         = {2017},
}