1. Stem Cells and Regenerative Medicine
Download icon

Live cell-lineage tracing and machine learning reveal patterns of organ regeneration

  1. Oriol Viader-Llargués
  2. Valerio Lupperger
  3. Laura Pola-Morell
  4. Carsten Marr  Is a corresponding author
  5. Hernán López-Schier  Is a corresponding author
  1. Helmholtz Zentrum München, Germany
Tools and Resources
  • Cited 12
  • Views 4,110
  • Annotations
Cite this article as: eLife 2018;7:e30823 doi: 10.7554/eLife.30823

Abstract

Despite the intrinsically stochastic nature of damage, sensory organs recapitulate normal architecture during repair to maintain function. Here we present a quantitative approach that combines live cell-lineage tracing and multifactorial classification by machine learning to reveal how cell identity and localization are coordinated during organ regeneration. We use the superficial neuromasts in larval zebrafish, which contain three cell classes organized in radial symmetry and a single planar-polarity axis. Visualization of cell-fate transitions at high temporal resolution shows that neuromasts regenerate isotropically to recover geometric order, proportions and polarity with exceptional accuracy. We identify mediolateral position within the growing tissue as the best predictor of cell-fate acquisition. We propose a self-regulatory mechanism that guides the regenerative process to identical outcome with minimal extrinsic information. The integrated approach that we have developed is simple and broadly applicable, and should help define predictive signatures of cellular behavior during the construction of complex tissues.

Article and author information

Author details

  1. Oriol Viader-Llargués

    Unit Sensory Biology and Organogenesis, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.

  2. Valerio Lupperger

    Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.

  3. Laura Pola-Morell

    Unit Sensory Biology and Organogenesis, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.

  4. Carsten Marr

    Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
    For correspondence
    carsten.marr@helmholtz-muenchen.de
    Competing interests
    The authors declare that no competing interests exist.

  5. Hernán López-Schier

    Unit Sensory Biology and Organogenesis, Helmholtz Zentrum München, Neuherberg, Germany
    For correspondence
    hernan.lopez-schier@helmholtz-muenchen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7925-7439

Funding

European Research Council (2007_205095)

  • Hernán López-Schier

AGAUR (2009-SGR-305)

  • Hernán López-Schier

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

Ethics

Animal experimentation: Zebrafish were maintained under standard conditions. Experiments with wild-type, mutant and transgenic embryos of undetermined sex were conducted in accordance with institutional guidelines and under a protocol approved by the Ethical Committee of Animal Experimentation of the Parc de Recerca Biomedica de Barcelona, Spain, and protocol number Gz.:55.2-1-54-2532-202-2014 by the "Regierung von Oberbayern", Germany.

Reviewing Editor

  1. Tanya T. Whitfield, University of Sheffield, United Kingdom

Publication history

  1. Received: July 27, 2017
  2. Accepted: March 28, 2018
  3. Accepted Manuscript published: March 29, 2018 (version 1)
  4. Version of Record published: April 17, 2018 (version 2)
  5. Version of Record updated: April 18, 2018 (version 3)

Copyright

© 2018, Viader-Llargués 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

  • 4,110
    Page views
  • 695
    Downloads
  • 12
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, 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)

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

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

Categories and tags

Research organism

Further reading

    1. Stem Cells and Regenerative Medicine

    Ecdysone steroid hormone remote controls intestinal stem cell fate decisions via the PPARγ-homolog Eip75B in Drosophila

    Lisa Zipper et al.
    Research Article

    Developmental studies revealed fundamental principles on how organ size and function is achieved, but less is known about organ adaptation to new physiological demands. In fruit flies, juvenile hormone (JH) induces intestinal stem cell (ISC) driven absorptive epithelial expansion balancing energy uptake with increased energy demands of pregnancy. Here, we show 20-Hydroxy-Ecdysone (20HE)-signaling controlling organ homeostasis with physiological and pathological implications. Upon mating, 20HE titer in ovaries and hemolymph are increased and act on nearby midgut progenitors inducing Ecdysone-induced-protein-75B (Eip75B). Strikingly, the PPARγ-homologue Eip75B drives ISC daughter cells towards absorptive enterocyte lineage ensuring epithelial growth. To our knowledge, this is the first time a systemic hormone is shown to direct local stem cell fate decisions. Given the protective, but mechanistically unclear role of steroid hormones in female colorectal cancer patients, our findings suggest a tumor-suppressive role for steroidal signaling by promoting postmitotic fate when local signaling is deteriorated.

    1. Neuroscience
    2. Stem Cells and Regenerative Medicine

    Activation of a neural stem cell transcriptional program in parenchymal astrocytes

    Jens P Magnusson et al.
    Research Article

    Adult neural stem cells, located in discrete brain regions, generate new neurons throughout life. These stem cells are specialized astrocytes, but astrocytes in other brain regions do not generate neurons under physiological conditions. After stroke, however, striatal astrocytes undergo neurogenesis in mice, triggered by decreased Notch signaling. We used single-cell RNA sequencing to characterize neurogenesis by Notch-depleted striatal astrocytes in vivo. Striatal astrocytes were located upstream of neural stem cells in the neuronal lineage. As astrocytes initiated neurogenesis, they became transcriptionally very similar to subventricular zone stem cells, progressing through a near-identical neurogenic program. Surprisingly, in the non-neurogenic cortex, Notch-depleted astrocytes also initiated neurogenesis. Yet, these cortical astrocytes, and many striatal ones, stalled before entering transit-amplifying divisions. Infusion of epidermal growth factor enabled stalled striatal astrocytes to resume neurogenesis. We conclude that parenchymal astrocytes are latent neural stem cells and that targeted interventions can guide them through their neuronal differentiation.

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine

    Stem cell niche exit in C. elegans via orientation and segregation of daughter cells by a cryptic cell outside the niche

    Kacy L Gordon et al.
    Research Article

    Stem cells reside in and rely upon their niche to maintain stemness but must balance self-renewal with the production of daughters that leave the niche to differentiate. We discovered a mechanism of stem cell niche exit in the canonical C. elegans distal tip cell (DTC) germ stem cell niche mediated by previously unobserved, thin, membranous protrusions of the adjacent somatic gonad cell pair (Sh1). A disproportionate number of germ cell divisions were observed at the DTC-Sh1 interface. Stem-like and differentiating cell fates segregated across this boundary. Spindles polarized, pairs of daughter cells oriented between the DTC and Sh1, and Sh1 grew over the Sh1-facing daughter. Impeding Sh1 growth by RNAi to cofilin and Arp2/3 perturbed the DTC-Sh1 interface, reduced germ cell proliferation, and shifted a differentiation marker. Because Sh1 membrane protrusions eluded detection for decades, it is possible that similar structures actively regulate niche exit in other systems.