"How Cell Populations Weed Out “Loser” Cells to Maintain Vitality is Revealed"

"How Cell Populations Weed Out “Loser” Cells to Maintain Vitality is Revealed"

Researchers shed light on how populations of cells eject individual cells with less beneficial characteristics, and that this process of “cell competition” is not uniform but dependent on local environment and particular proteins expressed in neighboring cells

Tokyo – Studies have suggested there is a process called “cell competition” whereby individual cells in a single population interact with each other, and those that are less fit or suitable for the environment are identified and removed. However, the mechanisms behind this competition, the reasons for it, and the criteria that determine whether cells win or lose in it have remained unclear.

Researchers centered at Tokyo Medical and Dental University (TMDU ) have now shown how a protein called YAP is particularly influential in determining the fate of cells that undergo this competition, and that the assignment of a “loser” status to a cell in this process depends on a range of factors including the expression of certain proteins in adjacent cells .

Fig : Schematic illustration of the proposed molecular mechanism of apical extrusion of active YAP-expressing MDCK cells.
1) active YAP induces TEAD-dependent gene expression; 2) the gene expression activates PI3K and mTOR signals; 3) neighboring cells recognize the change; 4) filamin accumulation induces some pressure for apical extrusion of YAP active cells; on the other hand, 5) active Ras or Src inhibits the apical extrusion.

The team established kidney cells in which the YAP protein labeled with a fluorescent marker was continuously highly expressed. They then mixed these cells at a ratio of 1:50 with normal cells, and allowed the mixture to form a layer only a single cell thick. The fluorescent labeling allowed the team to see under a microscope whether the YAP-overexpressing cells remained in the cell layer or were forced out.

“Initially, the kidney cells with high levels of YAP were ‘losers’ in the cell competition against their normal peers,” corresponding author Hiroshi Nishina says. “However, when we changed the expression profile of their neighbors, the result of the competition changed and high-YAP cells became the victors.”

The research team also revealed which parts of the YAP protein are involved in determining the fate of cells in cell competition. When they removed a particular domain and a binding motif from the YAP protein by site directed mutagenesis, the rate of removal of YAP-overexpressing cells from the monolayer decreased markedly.

“Similar to the way immune cells interact with foreign cells to purge them from the body, ‘cell competition’ appears to be a way for dysfunctional or suboptimal cells to be removed from tissues and organs,” first author Takanori Chiba says. “We now have a much better understanding of how this happens and that a range of factors determine which cells are selected for removal.”

The findings also indicate that the expression of two proteins called vimentin and filamin in adjacent cells is particularly important for cell fate. These proteins are known to function in determining cell shape and migration, suggesting that they could be appropriate subjects of future study to shed more light on how tissues and organs weed out ‘loser’ cells in order to function as effectively as possible.

The article “MDCK cells expressing constitutively active Yes-associated protein (YAP) undergo apical extrusion depending on neighboring cell status” was published in Scientific Reports at DOI: 10.1038/srep28383

Release Summary Text:

Tokyo Medical and Dental University (TMDU) researchers clarified how suboptimal cells within tissues are weeded out by “cell competition.” They showed that overexpression of the YAP protein within kidney cells led to these cells’ ejection from a monolayer dominated by normal equivalent cells. However, YAP-overexpressing cells became “winners” in this competition when the expression profiles of neighboring cells were manipulated. The findings suggest numerous factors in the microenvironment determine the fate of cells in cell competition.

Correspondence to:

Hiroshi NISHINA PhD, Professor
Department of Developmental and Regenerative Biology,
Medical Research Institute,
Tokyo Medical and Dental University (TMDU)
Phone:+81-3-5803-4659 Fax:+81-3-5803-0272
E-mail: nishina.dbio (at) mri.tmd.ac.jp