Abstract

Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated by a number of intrinsic and extrinsic mechanisms. Here we provide several lines of evidence to demonstrate that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis. Furthermore, lactate generation appears to be critical for the activation of HFSCs as deletion of lactate dehydrogenase (Ldha) prevented their activation. Conversely, genetically promoting lactate production in HFSCs through mitochondrial pyruvate carrier 1 (Mpc1) deletion accelerated their activation and the hair cycle. Finally, we identify small molecules that increase lactate production by stimulating Myc levels or inhibiting Mpc1 carrier activity and can topically induce the hair cycle. These data suggest that HFSCs maintain a metabolic state that allows them to remain dormant and yet quickly respond to appropriate proliferative stimuli.

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Acknowledgements

We would like to acknowledge the significant technical support of M. Neebe, J. Cinkornpumin and A. Liu on this project. We are also particularly grateful to members of the Banerjee laboratory for guidance and development of the Ldh activity assay. A.F. and A.C.W. were supported by a fellowship from the Eli and Edythe Broad Center for Regenerative Medicine at UCLA. A.C.W. and M.G. were supported by a fellowship from the Tumor Cell Biology programme at UCLA (NIH). A.C.W. was also supported by a training grant from CIRM. D.J. was supported by awards from a New Idea Award from the Leukemia Lymphoma Society, the Jonsson Comprehensive Cancer Center, the UCLA Clinical Translational Science Institute UL1TR000124, the Prostate Cancer SPORE at UCLA P50 CA092131, and the Eli & Edythe Broad Center for Regenerative Medicine & Stem Cell Research. N.A.G. is a postdoctoral trainee supported by the UCLA Scholars in Oncologic Molecular Imagining program (NCI/NIH grant R25T CA098010). A.S.K. was supported by a UCLA Dissertation Year Fellowship. H.A.C. was supported by National Institute of General Medical Sciences R01-GM081686 and R01-GM0866465. J.R. was supported by NIH (RO1GM094232). H.R.C. was supported by a Research Scholar Grant, RSG-16-111-01-MPC, from the American Cancer Society and the Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and Rose Hills Foundation Research Award. W.E.L. was supported by NIH-NIAMS (5R01AR57409), an Impact award from CTSI and the Jonsson Comprehensive Cancer Foundation, and The Gaba Fund through the Eli & Edythe Broad Center of Regenerative Medicine at UCLA.

Author information

Affiliations

  1. Department of Molecular Cell and Developmental Biology, UCLA, 90095, USA

    • Aimee Flores
    • , David Jelinek
    • , Matilde Miranda
    • , Hilary A. Coller
    •  & William E. Lowry
  2. Eli and Edythe Broad Center for Regenerative Medicine, UCLA, 90095, USA

    • Aimee Flores
    • , Hilary A. Coller
    • , Heather R. Christofk
    •  & William E. Lowry
  3. Molecular Biology Institute, UCLA, 90095, USA

    • Aimee Flores
    • , Hilary A. Coller
    •  & William E. Lowry
  4. Department of Biochemistry, University of Utah, 84322, USA

    • John Schell
    •  & Jared Rutter
  5. Department of Molecular and Medical Pharmacology, UCLA, 90095, USA

    • Abigail S. Krall
    • , Daniel Braas
    • , Nicholas A. Graham
    • , Thomas Graeber
    •  & Heather R. Christofk
  6. Stanford School of Medicine, Stanford University, 94305, USA

    • Melina Grigorian
  7. UCLA Metabolomics Center, UCLA, 90095, USA

    • Daniel Braas
    •  & Heather R. Christofk
  8. School of Veterinary Medicine, Cornell University, 14853, USA

    • Andrew C. White
  9. Mork Family Department of Chemical Engineering, University of Southern California, 90089, USA

    • Jessica L. Zhou
    •  & Nicholas A. Graham
  10. Crump Institute for Molecular Imaging, UCLA, 90095, USA

    • Thomas Graeber
  11. Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Cancer Center, Harvard Medical School, 02215, USA

    • Pankaj Seth
  12. Broad Center for Regenerative Medicine, University of Southern California, 90089, USA

    • Denis Evseenko
  13. Jonsson Comprehensive Cancer Center, UCLA, 90095, USA

    • Hilary A. Coller
    • , Heather R. Christofk
    •  & William E. Lowry
  14. Department of Biological Chemistry, UCLA, 90095, USA

    • Hilary A. Coller
    •  & Heather R. Christofk
  15. Howard Hughes Medical Institute, 20815, USA

    • Jared Rutter

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Contributions

A.F., J.S., A.S.K., D.J., M.M., M.G. and D.B. performed experiments. A.F., A.S.K., J.L.Z., N.A.G. performed analysis and compiled data. P.S., D.E. and J.R. provided key reagents essential to the work. T.G. and H.A.C. provided important insight and advice. H.R.C. and W.E.L. provided oversight and were financially responsible for the work. A.F., H.R.C. and W.E.L. were responsible for assembling the figures and writing the manuscript.

Competing interests

The use of RCGD423 to promote hair growth is covered by a provisional patent application filed by UC Regents and this technology has been licensed by Carthronix LLC. W.E.L. is a member of the board of advisers and a shareholder of Carthronix LLC. None of the work in this study was supported by Carthronix. The use of UK-5099 to promote hair growth is covered by a separate provisional patent filed by UC Regents with W.E.L. and H.R.C. as inventors.

Corresponding authors

Correspondence to Heather R. Christofk or William E. Lowry.

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