A multi-scale model for hair follicles reveals heterogeneous domains driving rapid spatiotemporal hair growth patterning

  1. Qixuan Wang
  2. Ji Won Oh
  3. Hye-Lim Lee
  4. Anukriti Dhar
  5. Tao Peng
  6. Raul Ramos
  7. Christian Fernando Guerrero-Juarez
  8. Xiaojie Wang
  9. Ran Zhao
  10. Xiaoling Cao
  11. Jonathan Le
  12. Melisa A Fuentes
  13. Shelby C Jocoy
  14. Antoni R Rossi
  15. Brian Vu
  16. Kim Pham
  17. Xiaoyang Wang
  18. Nanda Maya Mali
  19. Jung Min Park
  20. June-Hyug Choi
  21. Hyunsu Lee
  22. Julien Legrand
  23. Eve Kandyba
  24. Jung Chul Kim
  25. Moonkyu Kim
  26. John Foley
  27. Zhengquan Yu
  28. Krzysztof Kobielak
  29. Bogi Andersen
  30. Kiarash Khosrotehrani
  31. Qing Nie  Is a corresponding author
  32. Maksim V Plikus  Is a corresponding author
  1. University of California, Irvine, United States
  2. School of Medicine, Kyungpook National University, Republic of Korea
  3. School of Medicine, Kyungpook National University, Korea (South), Republic of
  4. University of Queensland Diamantina Institute, Australia
  5. University of Southern California, United States
  6. Kyungpook National University Hospital, Republic of Korea
  7. Indiana University School of Medicine, United States
  8. College of Biological Sciences, China Agricultural University, China

Abstract

The control principles behind robust cyclic regeneration of hair follicles (HFs) remain unclear. Using multi-scale modeling we show that coupling inhibitors and activators with physical growth of HFs is sufficient to drive periodicity and excitability of hair regeneration. Model simulations and experimental data reveal that mouse skin behaves as a heterogeneous regenerative field, composed of anatomical domains where HFs have distinct cycling dynamics. Interactions between fast-cycling chin and ventral HFs and slow-cycling dorsal HFs produce bilaterally symmetric patterns. Ear skin behaves as a hyper-refractory domain with HFs in extended rest phase. Such hyper-refractivity relates to high levels of BMP ligands and WNT antagonists, in part expressed by ear-specific cartilage and muscle. Hair growth stops at the boundaries with hyper-refractory ears and anatomically discontinuous eyelids, generating wave-breaking effects. We posit that similar mechanisms for coupled regeneration with dominant activator, hyper-refractory, and wave-breaker regions can operate in other actively renewing organs.

Data availability

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Qixuan Wang

    Department of Mathematics, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ji Won Oh

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5742-5120
  3. Hye-Lim Lee

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Anukriti Dhar

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Tao Peng

    Department of Mathematics, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Raul Ramos

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Christian Fernando Guerrero-Juarez

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Xiaojie Wang

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Ran Zhao

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Xiaoling Cao

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Jonathan Le

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Melisa A Fuentes

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Shelby C Jocoy

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Antoni R Rossi

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Brian Vu

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Kim Pham

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Xiaoyang Wang

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Nanda Maya Mali

    Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  19. Jung Min Park

    Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  20. June-Hyug Choi

    Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  21. Hyunsu Lee

    Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  22. Julien Legrand

    Experimental Dermatology Group, University of Queensland Diamantina Institute, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  23. Eve Kandyba

    Department of Pathology, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9219-5284
  24. Jung Chul Kim

    Hair Transplantation Center, Kyungpook National University Hospital, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  25. Moonkyu Kim

    Hair Transplantation Center, Kyungpook National University Hospital, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  26. John Foley

    Department of Dermatology, Medical Sciences Program, Indiana University School of Medicine, Bloomington, United States
    Competing interests
    The authors declare that no competing interests exist.
  27. Zhengquan Yu

    State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8696-2013
  28. Krzysztof Kobielak

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  29. Bogi Andersen

    Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7181-2768
  30. Kiarash Khosrotehrani

    Experimental Dermatology Group, University of Queensland Diamantina Institute, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  31. Qing Nie

    Department of Mathematics, University of California, Irvine, Irvine, United States
    For correspondence
    qnie@math.uci.edu
    Competing interests
    The authors declare that no competing interests exist.
  32. Maksim V Plikus

    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, United States
    For correspondence
    plikus@uci.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8845-2559

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR067273)

  • Maksim V Plikus

National Research Foundation of Korea (2016R1C1B1015211)

  • Ji Won Oh

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR061552)

  • Krzysztof Kobielak

National Health and Medical Research Council (1023371)

  • Kiarash Khosrotehrani

National Science Foundation (DGE-1321846)

  • Christian Fernando Guerrero-Juarez

National Institute of General Medical Sciences (GM055246)

  • Christian Fernando Guerrero-Juarez

Pew Charitable Trusts (29641)

  • Maksim V Plikus

National Science Foundation (DMS 1161621)

  • Qing Nie

National Cancer Institute (T32-CA009054)

  • Hye-Lim Lee

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR056439)

  • Bogi Andersen

National Science Foundation (DMS 1562176)

  • Qing Nie

National Institute of General Medical Sciences (P50-GM076516)

  • Qing Nie

National Institute of General Medical Sciences (R01-GM107264)

  • Qing Nie

National Institute of Neurological Disorders and Stroke (R01-NS095355)

  • Qing Nie

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2012-3054 and #2013-3081) of the University of California, Irvine.

Reviewing Editor

  1. Valerie Horsley, Yale University, United States

Publication history

  1. Received: October 28, 2016
  2. Accepted: June 29, 2017
  3. Accepted Manuscript published: July 11, 2017 (version 1)
  4. Version of Record published: September 22, 2017 (version 2)

Copyright

© 2017, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 7,124
    Page views
  • 1,209
    Downloads
  • 34
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Qixuan Wang
  2. Ji Won Oh
  3. Hye-Lim Lee
  4. Anukriti Dhar
  5. Tao Peng
  6. Raul Ramos
  7. Christian Fernando Guerrero-Juarez
  8. Xiaojie Wang
  9. Ran Zhao
  10. Xiaoling Cao
  11. Jonathan Le
  12. Melisa A Fuentes
  13. Shelby C Jocoy
  14. Antoni R Rossi
  15. Brian Vu
  16. Kim Pham
  17. Xiaoyang Wang
  18. Nanda Maya Mali
  19. Jung Min Park
  20. June-Hyug Choi
  21. Hyunsu Lee
  22. Julien Legrand
  23. Eve Kandyba
  24. Jung Chul Kim
  25. Moonkyu Kim
  26. John Foley
  27. Zhengquan Yu
  28. Krzysztof Kobielak
  29. Bogi Andersen
  30. Kiarash Khosrotehrani
  31. Qing Nie
  32. Maksim V Plikus
(2017)
A multi-scale model for hair follicles reveals heterogeneous domains driving rapid spatiotemporal hair growth patterning
eLife 6:e22772.
https://doi.org/10.7554/eLife.22772
  1. Further reading

Further reading

    1. Computational and Systems Biology
    2. Evolutionary Biology
    Serkan Sayin, Brittany Rosener ... Amir Mitchell
    Research Advance

    Drug metabolism by the microbiome can influence anti-cancer treatment success. We previously suggested that chemotherapies with antimicrobial activity can select for adaptations in bacterial drug metabolism that can inadvertently influence the host's chemoresistance. We demonstrated that evolved resistance against fluoropyrimidine chemotherapy lowered its efficacy in worms feeding on drug-evolved bacteria (Rosener et al., 2020). Here we examine a model system that captures local interactions that can occur in the tumor microenvironment. Gammaproteobacteria colonizing pancreatic tumors can degrade the nucleoside-analog chemotherapy gemcitabine and, in doing so, can increase the tumor's chemoresistance. Using a genetic screen in Escherichia coli, we mapped all loss-of-function mutations conferring gemcitabine resistance. Surprisingly, we infer that one third of top resistance mutations increase or decrease bacterial drug breakdown and therefore can either lower or raise the gemcitabine load in the local environment. Experiments in three E. coli strains revealed that evolved adaptation converged to inactivation of the nucleoside permease NupC, an adaptation that increased the drug burden on co-cultured cancer cells. The two studies provide complementary insights on the potential impact of microbiome adaptation to chemotherapy by showing that bacteria-drug interactions can have local and systemic influence on drug activity.

    1. Computational and Systems Biology
    2. Neuroscience
    Andrew McKinney, Ming Hu ... Xiaolong Jiang
    Research Article

    The locus coeruleus (LC) houses the vast majority of noradrenergic neurons in the brain and regulates many fundamental functions including fight and flight response, attention control, and sleep/wake cycles. While efferent projections of the LC have been extensively investigated, little is known about its local circuit organization. Here, we performed large-scale multi-patch recordings of noradrenergic neurons in adult mouse LC to profile their morpho-electric properties while simultaneously examining their interactions. LC noradrenergic neurons are diverse and could be classified into two major morpho-electric types. While fast excitatory synaptic transmission among LC noradrenergic neurons was not observed in our preparation, these mature LC neurons connected via gap junction at a rate similar to their early developmental stage and comparable to other brain regions. Most electrical connections form between dendrites and are restricted to narrowly spaced pairs or small clusters of neurons of the same type. In addition, more than two electrically coupled cell pairs were often identified across a cohort of neurons from individual multi-cell recording sets that followed a chain-like organizational pattern. The assembly of LC noradrenergic neurons thus follows a spatial and cell type-specific wiring principle that may be imposed by a unique chain-like rule.