Pathogenic shifts in endogenous microbiota impede tissue regeneration via distinct activation of TAK1/MKK/p38

  1. Christopher P Arnold
  2. M Shane Merryman
  3. Aleishia Harris-Arnold
  4. Sean A McKinney
  5. Chris W Seidel
  6. Sydney Loethen
  7. Kylie N Proctor
  8. Longhua Guo
  9. Alejandro Sánchez Alvarado  Is a corresponding author
  1. Stowers Institute for Medical Research, United States
  2. University of Missouri, United States
  3. Pittsburg State University, United States

Abstract

The interrelationship between endogenous microbiota, the immune system, and tissue regeneration is an area of intense research due to its potential therapeutic applications. We investigated this relationship in Schmidtea mediterranea, a model organism capable of regenerating any and all of its adult tissues. Microbiome characterization revealed a high Bacteroidetes to Proteobacteria ratio in healthy animals. Perturbations eliciting an expansion of Proteobacteria coincided with ectopic lesions and tissue degeneration. Culture of these bacteria yielded a strain of Pseudomonas capable of inducing progressive tissue degeneration. RNAi screening uncovered a TAK1 innate immune signaling module underlying compromised tissue homeostasis and regeneration during infection. TAK1/MKK/p38 signaling mediated opposing regulation of apoptosis during infection versus normal tissue regeneration. Given the complex role of inflammation in either hindering or supporting reparative wound healing and regeneration, this invertebrate model provides a basis for dissecting the duality of evolutionarily conserved inflammatory signaling in complex, multi-organ adult tissue regeneration.

Article and author information

Author details

  1. Christopher P Arnold

    Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    No competing interests declared.
  2. M Shane Merryman

    Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    No competing interests declared.
  3. Aleishia Harris-Arnold

    Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    No competing interests declared.
  4. Sean A McKinney

    Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    No competing interests declared.
  5. Chris W Seidel

    Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    No competing interests declared.
  6. Sydney Loethen

    University of Missouri, Kansas City, United States
    Competing interests
    No competing interests declared.
  7. Kylie N Proctor

    Pittsburg State University, Pittsburg, United States
    Competing interests
    No competing interests declared.
  8. Longhua Guo

    Stowers Institute for Medical Research, Kansas City, United States
    Competing interests
    No competing interests declared.
  9. Alejandro Sánchez Alvarado

    Stowers Institute for Medical Research, Kansas City, United States
    For correspondence
    asa@stowers.org
    Competing interests
    Alejandro Sánchez Alvarado, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1966-6959

Funding

Howard Hughes Medical Institute

  • Alejandro Sánchez Alvarado

National Institute of General Medical Sciences (R37GM057260)

  • Alejandro Sánchez Alvarado

Stowers Institute for Medical Research

  • Alejandro Sánchez Alvarado

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

Reviewing Editor

  1. Richard Losick, Harvard University, United States

Publication history

  1. Received: April 8, 2016
  2. Accepted: July 19, 2016
  3. Accepted Manuscript published: July 21, 2016 (version 1)
  4. Accepted Manuscript updated: July 28, 2016 (version 2)
  5. Version of Record published: August 22, 2016 (version 3)

Copyright

© 2016, Arnold 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

  • 5,101
    Page views
  • 932
    Downloads
  • 61
    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. Christopher P Arnold
  2. M Shane Merryman
  3. Aleishia Harris-Arnold
  4. Sean A McKinney
  5. Chris W Seidel
  6. Sydney Loethen
  7. Kylie N Proctor
  8. Longhua Guo
  9. Alejandro Sánchez Alvarado
(2016)
Pathogenic shifts in endogenous microbiota impede tissue regeneration via distinct activation of TAK1/MKK/p38
eLife 5:e16793.
https://doi.org/10.7554/eLife.16793

Further reading

    1. Stem Cells and Regenerative Medicine
    Rachel Warren, Handeng Lyu ... Stijn P De Langhe
    Research Article Updated

    Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicates that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF pathogenesis. Loss of alveolar type 2 (AT2) stem cells or mutations that either impair their self-renewal and/or impair their differentiation into AT1 cells can serve as a trigger of pulmonary fibrosis. Recent reports indicate increased YAP activity in respiratory epithelial cells in IPF lungs. Individual IPF epithelial cells with aberrant YAP activation in bronchiolized regions frequently co-express AT1, AT2, conducting airway selective markers and even mesenchymal or EMT markers, demonstrating ‘indeterminate’ states of differentiation and suggesting that aberrant YAP signaling might promote pulmonary fibrosis. Yet, Yap and Taz have recently also been shown to be important for AT1 cell maintenance and alveolar epithelial regeneration after Streptococcus pneumoniae-induced injury. To investigate how epithelial Yap/Taz might promote pulmonary fibrosis or drive alveolar epithelial regeneration, we inactivated the Hippo pathway in AT2 stem cells resulting in increased nuclear Yap/Taz, and found that this promotes their alveolar regenerative capacity and reduces pulmonary fibrosis following bleomycin injury by pushing them along the AT1 cell lineage. Vice versa, inactivation of both Yap1 and Wwtr1 (encoding Taz) or Wwtr1 alone in AT2 cell stem cells impaired alveolar epithelial regeneration and resulted in increased pulmonary fibrosis upon bleomycin injury. Interestingly, the inactivation of only Yap1 in AT2 stem cells promoted alveolar epithelial regeneration and reduced pulmonary fibrosis. Together, these data suggest that epithelial Yap promotes, and epithelial Taz reduces pulmonary fibrosis suggesting that targeting Yap but not Taz-mediated transcription might help promote AT1 cell regeneration and treat pulmonary fibrosis.

    1. Cell Biology
    2. Stem Cells and Regenerative Medicine
    Rafael Soares Godoy, Nicholas D Cober ... Duncan J Stewart
    Research Article Updated

    We sought to define the mechanism underlying lung microvascular regeneration in a model of severe acute lung injury (ALI) induced by selective lung endothelial cell ablation. Intratracheal instillation of DT in transgenic mice expressing human diphtheria toxin (DT) receptor targeted to ECs resulted in ablation of >70% of lung ECs, producing severe ALI with near complete resolution by 7 days. Using single-cell RNA sequencing, eight distinct endothelial clusters were resolved, including alveolar aerocytes (aCap) ECs expressing apelin at baseline and general capillary (gCap) ECs expressing the apelin receptor. At 3 days post-injury, a novel gCap EC population emerged characterized by de novo expression of apelin, together with the stem cell marker, protein C receptor. These stem-like cells transitioned at 5 days to proliferative endothelial progenitor-like cells, expressing apelin receptor together with the pro-proliferative transcription factor, Foxm1, and were responsible for the rapid replenishment of all depleted EC populations by 7 days post-injury. Treatment with an apelin receptor antagonist prevented ALI resolution and resulted in excessive mortality, consistent with a central role for apelin signaling in EC regeneration and microvascular repair. The lung has a remarkable capacity for microvasculature EC regeneration which is orchestrated by newly emergent apelin-expressing gCap endothelial stem-like cells that give rise to highly proliferative, apelin receptor-positive endothelial progenitors responsible for the regeneration of the lung microvasculature.