Differences in mitochondrial activity trigger cell competition during early mouse development
Preprint posted on January 15, 2020 https://www.biorxiv.org/content/10.1101/2020.01.15.900613v1.full#F10
Common traits of losers: mitochondrial dysfunction triggers elimination of loser cells by cell competition during early mouse post-implantation development
Selected by Teresa RayonCategories: cell biology, developmental biology, molecular biology
Summary:
Cell competition is the selective elimination of less fit but viable cells when in the presence of more fit cells. Even though several molecular mechanisms have been shown to account for cell competition, what features identify less fit cells (losers) remains largely elusive, and it is not known whether these are shared in various cell competition contexts. In this preprint, the Rodriguez lab show that impaired mitochondrial function is a common feature of loser cells, and demonstrate that perturbations in mitochondrial function are sufficient to drive cell competition. Moreover, by linking cell competition and mitochondrial activity, this work centers fitness on mitochondrial performance.
In a remarkable technical effort, Lima, Lubatti et al. perform single-cell transcriptomics in early postimplantation mouse embryos treated with a caspase inhibitor that blocks apoptosis. The comparison between cells in these embryos and untreated embryos allowed them to identify a cluster composed only of cells coming from the caspase-treated embryos. This cluster contained differentially regulated genes characteristic of cell competition (cell death and survival, protein synthesis and nucleic acids), which defined a loser signature. Analysing this signature, they found that the top two misregulated pathways are related to mitochondrial function (mitochondrial dysfunction and oxidative phosphorylation). In addition, this signature allows them to analyze the cellular identity of loser cells: dying cells represent a mis-patterned state, perhaps similar to cell competition during preimplantation development (1). Next, the authors characterized mitochondrial activity in other cell competition models, and identify mitochondrial dysfunction in a range of different loser cells. In addition, they show that disrupting mitochondrial dynamics is sufficient to drive cell competition in mitochondrial fusion and fission mutant stem cells (Drp1-/- and Mfn2-/-). Finally, the authors show that loser cells accumulate mutations in their mitochondrial DNA (mtDNA), and that the ability to drive cell competition can be determined by small changes in mitochondrial DNA sequences. Altogether, this work highlights that cell competition is directly coupled to mitochondrial performance to ensure an optimal metabolic output in preparation for gastrulation.
Why I chose the paper:
Cell competition has emerged as a quality control mechanism that selects the fittest cells in the embryo and the adult. I like that the authors’ model system for cell competition is the early post implantation mouse embryo. This model is one of the few where an endogenous role for cell competition has been shown (2, 3). Interestingly, the need for cell competition in this context has been explained as a quality checkpoint in mammals where a number of progenitors can be rapidly eliminated and rapidly replenished without damaging embryo development.
Multiple pathways have been shown to trigger cell competition, and those occurring in the early postimplantation embryo have been related to metabolic cell competition (4). I selected this preprint because the authors identify for the first time that mitochondrial function is the unifying component for defining fitness in cell competition, irrespective of the triggering pathway.
I find some of the challenging experiments they performed remarkably elegant. In particular, the identification of increased mtDNA heteroplasmy in losing cells from their scRNA-seq analysis that suggests that cell competition eliminates deleterious mtDNA mutations and reduces the frequency of mtDNA variants. Likewise, the identification of changes in oxidative phosphorylation and cytokine activity in stem cell lines with different mtDNA composition, and their performance in cell competition experiments highlights that cells are selected according to their mitochondrial activity to ensure efficient growth during early development.
How this work moves the field forward:
The cell competition field has become increasingly popular over the last 10 years. Multiple mechanisms account for cell competition in a variety of organs and organisms, from Drosophila to mammals. However, characterization of endogenous cell competition can be hindered because most of the pathways involved correspond to basic cellular functions (cell death and proliferation, growth, etc.), and it is difficult to ascertain a specific role for cell competition. This work highlights how mitochondrial activity may be a general mechanism that determines fitness in a wide range of systems in a context where endogenous cell competition takes place.
In addition, metabolism is intimately connected to the environment, and it therefore provides a link between genotype and environmental cues. In future studies, it will be interesting to further explore this interaction and the role cell competition plays therein.
References :
- M. Hashimoto, H. Sasaki, Epiblast Formation by TEAD-YAP-Dependent Expression of Pluripotency Factors and Competitive Elimination of Unspecified Cells. Developmental Cell. 50, 139-154.e5 (2019).
- C. Clavería, G. Giovinazzo, R. Sierra, M. Torres, Myc-driven endogenous cell competition in the early mammalian embryo. Nature. 500, 39–44 (2013).
- M. Sancho, A. Di-Gregorio, N. George, S. Pozzi, J. M. Sánchez, B. Pernaute, T. A. Rodríguez, Competitive Interactions Eliminate Unfit Embryonic Stem Cells at the Onset of Differentiation. Developmental Cell. 26, 19–30 (2013).
- C. Clavería, M. Torres, Cell Competition: Mechanisms and Physiological Roles. Annual Review of Cell and Developmental Biology. 32, 411–439 (2016).
Questions to the authors:
Q1. The “losing phenotype” (cluster 4) cells could only be identified in caspase-inhibited embryos, but not in DMSO-treated embryos. This may mean that this phenotype is an exacerbation of the signature of loser cells, and that the “intermediate” phenotype could be the endogenous “losing phenotype”. How overlapping do the authors think that the “intermediate cluster” is to the “losing phenotype”? What is unique to the “intermediate cluster”?
Q2. Since metabolic activity explains many models of cell competition, how do the authors think mitochondrial performance is sensed amongst neighbors?
Q3. Thinking about mitochondria composition in cells, loser cells contain mitochondria that accumulate mutations in their mtDNA. Since the authors have a collection of cells that contain different types of mitochondria, and those show different outcomes in cell competition, do the authors think that the “fittest” cells are less sensitive to mutations in their mtDNA?
Posted on: 29th January 2020
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