Stem Cells: More than just a pool

An intricate stem cell niche boundary formed by finger-like extensions generates asymmetry in stem cell divisions.
  1. Amanda Cinquin  Is a corresponding author
  2. Olivier Cinquin  Is a corresponding author
  1. Department of Developmental and Cell Biology, Center for Complex Biological Systems, University of California, Irvine, United States

Stem cells have the ability to divide and self-renew or specialize into many different types of cells that replenish tissues and organs. Historically, and based largely on blood stem cells, divisions have been thought to be asymmetric, resulting in two daughter cells with different fates: an identical, slow-cycling stem cell and a faster-cycling progenitor cell committed to differentiation. However, self-renewal of many tissues, such as the intestine, is ensured by cells that do not display strong division asymmetry and are instead organized as pools of progenitor cells. Daughter cells of these progenitors frequently do not appear to differ in their likelihood to self-renew or specialize (Post and Clevers, 2019).

Establishing the design principles underlying such progenitor pools is key to understanding how continuous self-renewal is maintained. Now, in eLife, Kacy Gordon and colleagues from the University of North Carolina and Duke University report new insights about stem cell division in the nematode Caenorhabditis elegans (Gordon et al., 2020).

In C. elegans, germ stem cells – which ensure the production of oocytes and sperm – reside at one end of tube-shaped gonads in what is known as the progenitor zone. The progenitor zone is capped by a large cell called the distal tip cell. The distal tip cell controls the proliferation of germ stem cells, and its finger-like extensions are thought to communicate with these cells (Fitzgerald and Greenwald, 1995; Byrd et al., 2014). Proximal sheath cells (Sh1 cells) surround the gonads and wrap the differentiating germ stem cells exiting the progenitor zone.

Germ stem cells within the progenitor zone show some variation in specialization (the cells closest to the proximal end of the gonads start expressing genes associated with the differentiation of reproductive cells). But the orientation of progenitor division was reported to be largely random, compatible with the idea that the progenitor zone, or at least a distal portion thereof, forms a ‘bag’ of mostly equivalent proliferating cells – with the most proximal being randomly pushed out and differentiating. The speed of the cell cycle is largely similar among progenitors, apparently furthering the notion that the differentiation process is not controlled by division asymmetry (Maciejowski et al., 2006; Crittenden et al., 2006; Jaramillo-Lambert et al., 2007; Chiang et al., 2015; Rosu and Cohen-Fix, 2017).

To investigate how the cell fate of germ stem cells is regulated, Gordon et al. used fluorescent labeling of both the distal tip cell and the Sh1 cells and tracked the dividing germ stem cells. This revealed that both the distal tip cell and Sh1 cells intercalate long protrusions that contact the germ stem cells (Figure 1a). Unexpectedly, most cell divisions happened at the distal tip cell-Sh1 interface. Most strikingly, these divisions were often asymmetrical, with one daughter cell staying in contact with the distal tip cell and the other one with Sh1 cells – turning the idea on its head that the progenitor zone is a pool of randomly proliferating cells. Manipulation of the cytoskeleton-related gene expression further suggested that a tightly knit interface between the distal tip cell and Sh1 cells may be necessary for robust proliferation. However, this does not rule out that this interface could also respond to signals from dividing germ stem cells. This interface may also play a role in positioning gene expression patterns within the progenitor zone.

Stem cell division in Caenorhabditis elegans.

(A) In C. elegans, germ stem cells reside in a niche formed by the distal tip cell (DTC) and are wrapped by the proximal sheath cells (Sh1) as they move proximally and differentiate. The DTC forms protrusions that may communicate with germ stem cells. Gordon et al. discovered that Sh1 cells also have finger-like extensions that intercalate with the DTC and contact progenitors. (B) Cell division takes place in three different compartments within the progenitor zone (PZ): one covered by the DTC (purple) , one at the interface of the DTC and Sh1 (orange), and one covered by Sh1 (green). Divisions are often asymmetric in that each daughter maintains contact with one of DTC or Sh1. (C) Germ cells contacting both the DTC and Sh1 cells contribute a substantial fraction of overall progenitor generation because they have a higher proportion of dividing cells to non-dividing cells compared to the other compartments.

The work of Gordon et al. illustrates that a niche is more than just a region that accommodates a given number of stem cells or that serves as a punctual source of a self-renewal signals (Schofield, 1978). Rather, these experiments have unearthed hidden layers of control and thus provide a stepping stone to future research unraveling unknown mechanisms underlying cell fate determination. For example, what is the purpose of asymmetric cell division in this specific area? Could the intricate shape of the niche enlarge the surface area and so increase the number of asymmetric divisions in this progenitor zone? This asymmetry, even if it does not anchor stem cells, could still shape clonal dynamics in a way that helps minimize mutations and prevent premature senescence of germline stem cells (Cairns, 2006; Chiang et al., 2015; Cinquin et al., 2016).

In the future, it will be important to study germ stem cells below the gonad surface, which may have different behaviors;, and to assay the impact of asymmetric division on the dynamics of stem cell clones. It remains to be seen if protrusions similar to those of the distal tip cell and those of other cell types such as embryonic stem cells (Ramírez-Weber and Kornberg, 1999; Inaba et al., 2015; Junyent et al., 2020), are a prevalent feature of stem cell niches. Such structures could have remained hidden because of imaging difficulties, and may represent a hub for asymmetric cell divisions in tissues currently viewed as lacking those features.

References

    1. Fitzgerald K
    2. Greenwald I
    (1995)
    Interchangeability of Caenorhabditis elegans DSL proteins and intrinsic signalling activity of their extracellular domains in vivo
    Development 121:4275–4282.
    1. Schofield R
    (1978)
    The relationship between the spleen colony-forming cell and the haemopoietic stem cell
    Blood Cells 4:7–25.

Article and author information

Author details

  1. Amanda Cinquin

    Amanda Cinquin is in the Department of Developmental and Cell Biology, Center for Complex Biological Systems, University of California, Irvine, United States

    For correspondence
    acinquin@uci.edu
    Competing interests
    No competing interests declared
  2. Olivier Cinquin

    Olivier Cinquin is in the Department of Developmental and Cell Biology, Center for Complex Biological Systems, University of California, Irvine, United States

    For correspondence
    ocinquin@uci.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4771-1857

Publication history

  1. Version of Record published: September 11, 2020 (version 1)

Copyright

© 2020, Cinquin and Cinquin

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

Metrics

  • 690
    Page views
  • 47
    Downloads
  • 0
    Citations

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

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. Amanda Cinquin
  2. Olivier Cinquin
(2020)
Stem Cells: More than just a pool
eLife 9:e61397.
https://doi.org/10.7554/eLife.61397

Further reading

    1. Cell Biology
    2. Developmental Biology
    Katelyn J Hoff et al.
    Research Article Updated

    Heterozygous, missense mutations in α- or β-tubulin genes are associated with a wide range of human brain malformations, known as tubulinopathies. We seek to understand whether a mutation’s impact at the molecular and cellular levels scale with the severity of brain malformation. Here, we focus on two mutations at the valine 409 residue of TUBA1A, V409I, and V409A, identified in patients with pachygyria or lissencephaly, respectively. We find that ectopic expression of TUBA1A-V409I/A mutants disrupt neuronal migration in mice and promote excessive neurite branching and a decrease in the number of neurite retraction events in primary rat neuronal cultures. These neuronal phenotypes are accompanied by increased microtubule acetylation and polymerization rates. To determine the molecular mechanisms, we modeled the V409I/A mutants in budding yeast and found that they promote intrinsically faster microtubule polymerization rates in cells and in reconstitution experiments with purified tubulin. In addition, V409I/A mutants decrease the recruitment of XMAP215/Stu2 to plus ends in budding yeast and ablate tubulin binding to TOG (tumor overexpressed gene) domains. In each assay tested, the TUBA1A-V409I mutant exhibits an intermediate phenotype between wild type and the more severe TUBA1A-V409A, reflecting the severity observed in brain malformations. Together, our data support a model in which the V409I/A mutations disrupt microtubule regulation typically conferred by XMAP215 proteins during neuronal morphogenesis and migration, and this impact on tubulin activity at the molecular level scales with the impact at the cellular and tissue levels.

    1. Cell Biology
    2. Developmental Biology
    Ivonne Margarete Sehring et al.
    Research Article

    Successful regeneration requires the coordinated execution of multiple cellular responses to injury. In amputated zebrafish fins, mature osteoblasts dedifferentiate, migrate towards the injury and form proliferative osteogenic blastema cells. We show that osteoblast migration is preceded by cell elongation and alignment along the proximodistal axis, which require actomyosin, but not microtubule turnover. Surprisingly, osteoblast dedifferentiation and migration can be uncoupled. Using pharmacological and genetic interventions, we found that NF-ĸB and retinoic acid signalling regulate dedifferentiation without affecting migration, while the complement system and actomyosin dynamics affect migration but not dedifferentiation. Furthermore, by removing bone at two locations within a fin ray, we established an injury model containing two injury sites. We found that osteoblasts dedifferentiate at and migrate towards both sites, while accumulation of osteogenic progenitor cells and regenerative bone formation only occur at the distal-facing injury. Together, these data indicate that osteoblast dedifferentiation and migration represent generic injury responses that are differentially regulated and can occur independently of each other and of regenerative growth. We conclude that successful fin bone regeneration appears to involve the coordinated execution of generic and regeneration-specific responses of osteoblasts to injury.