Hepatic Leukemia Factor Maintains Quiescence of Hematopoietic Stem Cells and Protects the Stem Cell Pool during Regeneration
Karolina Komorowska,
Alexander Doyle,
Martin Wahlestedt,
Agatheeswaran Subramaniam,
Shubhranshu Debnath,
Jun Chen,
Shamit Soneji,
Ben Van Handel,
Hanna K.A. Mikkola,
Kenichi Miharada,
David Bryder,
Jonas Larsson,
Mattias Magnusson
Affiliations
Karolina Komorowska
Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84, Lund, Sweden
Alexander Doyle
Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84, Lund, Sweden
Martin Wahlestedt
Molecular Hematology, Lund Stem Cell Center, Lund University, BMC A12, 221 84, Lund, Sweden
Agatheeswaran Subramaniam
Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84, Lund, Sweden
Shubhranshu Debnath
Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84, Lund, Sweden
Jun Chen
Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84, Lund, Sweden
Shamit Soneji
Molecular Hematology, Lund Stem Cell Center, Lund University, BMC A12, 221 84, Lund, Sweden
Ben Van Handel
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; CarthroniX, Inc., Tarzana, CA 91356, USA
Hanna K.A. Mikkola
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Kenichi Miharada
Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84, Lund, Sweden
David Bryder
Molecular Hematology, Lund Stem Cell Center, Lund University, BMC A12, 221 84, Lund, Sweden
Jonas Larsson
Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84, Lund, Sweden
Mattias Magnusson
Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84, Lund, Sweden; Corresponding author
Summary: 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. Keywords: HSC, transcription factor, HLF, quiescence, self-renewal, cell cycle, reconstitution, transplantation, 5FU, stress
