Abstract
Cells that grow together respond heterogeneously to stress even when they are genetically similar. Metabolism, a key determinant of cellular stress tolerance, may be one source of this phenotypic heterogeneity, however, this relationship is largely unclear. We used self‐establishing metabolically cooperating (SeMeCo) yeast communities, in which metabolic cooperation can be followed on the basis of genotype, as a model to dissect the role of metabolic cooperation in single‐cell heterogeneity. Cells within SeMeCo communities showed to be highly heterogeneous in their stress tolerance, while the survival of each cell under heat or oxidative stress, was strongly determined by its metabolic specialization. This heterogeneity emerged for all metabolite exchange interactions studied (histidine, leucine, uracil, and methionine) as well as oxidant (H2O2, diamide) and heat stress treatments. In contrast, the SeMeCo community collectively showed to be similarly tolerant to stress as wild‐type populations. Moreover, stress heterogeneity did not establish as sole consequence of metabolic genotype (auxotrophic background) of the single cell, but was observed only for cells that cooperated according to their metabolic capacity. We therefore conclude that phenotypic heterogeneity and cell to cell differences in stress tolerance are emergent properties when cells cooperate in metabolism.
Highlights
Metabolism and the stress response are two highly interdependent processes: metabolism determines the growth rate of cells, provides cofactors for the stress responsive machinery (i.e. nicotinamide adenine dinucleotide phosphate (NADPH) for antioxidant enzymes), and is a source of toxic or oxidizing molecules itself, while the stress response involves metabolic re-configuration [1,2,3,4]
When the self-establishing metabolically cooperating (SeMeCo) founder cell grows into a community, these plasmids are stochastically lost at a rate of ~2–4% per cell division so that, over time, the number of auxotrophic cells in the community increases
The wild type-like growth properties of SeMeCos allowed us to conclude that sharing of histidine, leucine, uracil and methionine metabolites is a natural property of yeast colonial growth [31]
Summary
Metabolism and the stress response are two highly interdependent processes: metabolism determines the growth rate of cells, provides cofactors for the stress responsive machinery (i.e. nicotinamide adenine dinucleotide phosphate (NADPH) for antioxidant enzymes), and is a source of toxic or oxidizing molecules itself, while the stress response involves metabolic re-configuration [1,2,3,4]. Www.biotechnology-journal.com www.biotecvisions.com co-growing cells establish substantial diversity, with some cells surviving and others dying upon application of the same perturbation [16,17,18,19,20] Such heterogeneity can be non-genotypic and, by enabling bet hedging strategies, positively influence the survival of the community in stress situations [21, 22]. Phenotypic heterogeneity can improve population fitness in large scale bioreactor processes where environmental fluctuations occur as a result of transient concentration gradients [29]. Despite these promising avenues of research, phenotypic variability gives rise to difficulties in controlling bioprocessing [30]. One cause of suboptimal productivity can be the presence of subpopulations exhibiting non-producer and low-producer phenotypes as a result of the metabolic state of the cell, such as its stage in the cell cycle or its interaction with other cells in the population [30, 31]
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