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Cell competition is a key mechanism by which tissues regulate cellular fitness and maintain homeostasis. In aging tissues, senescent cells show irreversibly arrested proliferation and yet persist and compete with proliferative non-senescent cells for space. How immune surveillance shapes this competition and regulates health and lifespan of such tissues remains poorly understood especially because of the multiscale nature of interactions.
To address this, we developed a multiscale modelling framework to study cell competition between senescent and non-senescent epithelial cells under immune-mediated clearance. At the population level, we formulated a system of ordinary differential equations (ODEs) describing competitive interactions among proliferative cells, senescent cells, and immune effectors, incorporating growth, senescence induction, immune recruitment, and senolysis. Analysis reveals regimes of competitive exclusion, coexistence, and senescent dominance driven by nonlinear feedbacks.
To capture the spatial aspects of such competitions, we constructed an agent-based Cellular Potts Model (CPM), in which cells compete locally for space and interact with immune cells. The CPM reveals spatial clustering of senescent cells and stochastic immune clearance absent in mean-field models. By comparing the ODE and CPM models, we aim to shed light on the role of spatial structure, crowding, and cell-niche adhesion, and softness, in immune-regulated competitions during tissue aging
Bibliography
@article{Gradeci_Bove_Vallardi_Lowe_Banerjee_Charras_2021, title={Cell-scale biophysical determinants of cell competition in epithelia}, volume={10}, ISSN={2050-084X}, url={https://elifesciences.org/articles/61011}, DOI={10.7554/eLife.61011}, abstractNote={How cells with different genetic makeups compete in tissues is an outstanding question in developmental biology and cancer research. Studies in recent years have revealed that cell competition can either be driven by short-range biochemical signalling or by long-range mechanical stresses in the tissue. To date, cell competition has generally been characterised at the population scale, leaving the single-cell-level mechanisms of competition elusive. Here, we use high time-resolution experimental data to construct a multi-scale agent-based model for epithelial cell competition and use it to gain a conceptual understanding of the cellular factors that governs competition in cell populations within tissues. We find that a key determinant of mechanical competition is the difference in homeostatic density between winners and losers, while differences in growth rates and tissue organisation do not affect competition end result. In contrast, the outcome and kinetics of biochemical competition is strongly influenced by local tissue organisation. Indeed, when loser cells are homogenously mixed with winners at the onset of competition, they are eradicated; however, when they are spatially separated, winner and loser cells coexist for long times. These findings suggest distinct biophysical origins for mechanical and biochemical modes of cell competition.}, journal={eLife}, author={Gradeci, Daniel and Bove, Anna and Vallardi, Giulia and Lowe, Alan R and Banerjee, Shiladitya and Charras, Guillaume}, year={2021}, month=may, pages={e61011}, language={en} }
@article{Michaels_Mahadevan_2023, title={Optimal intercellular competition in senescence and cancer}, volume={479}, ISSN={1364-5021, 1471-2946}, url={https://royalsocietypublishing.org/doi/10.1098/rspa.2023.0204}, DOI={10.1098/rspa.2023.0204}, abstractNote={Effective multicellularity requires both cooperation and competition between constituent cells. Cooperation involves sacrificing individual fitness in favour of that of the community, but excessive cooperation makes the community susceptible to senescence and ageing. Competition eliminates unfit senescent cells via natural selection and thus slows down ageing, but excessive competition makes the community susceptible to cheaters, as exemplified by cancer and cancer-like phenomena. These observations suggest that an optimal level of intercellular competition in a multicellular organism maximizes organismal vitality by delaying the inevitability of ageing. We quantify this idea using a statistical mechanical framework that leads to a generalized replicator dynamical system for the population of cells that changes their vitality and cooperation due to somatic mutations that make them susceptible to ageing and/or cancer. By accounting for the cost of cooperation and strength of competition in a minimal setting, we show that our model predicts an optimal value of competition that maximizes vitality and delays the inevitability of senescence or cancer. The results have implications for the design of strategies aimed at delaying ageing in biological, technical and social systems that exhibit similar processes.}, number={2276}, journal={Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences}, author={Michaels, Thomas C. T. and Mahadevan, L.}, year={2023}, month=aug, pages={20230204}, language={en} }
@article{Rebehn_Khalaji_KleinJan_Kleemann_Port_Paul_Huster_Nolte_Singh_Kwapich_et al._2023, title={The weakness of senescent dermal fibroblasts}, volume={120}, ISSN={0027-8424, 1091-6490}, url={https://pnas.org/doi/10.1073/pnas.2301880120}, DOI={10.1073/pnas.2301880120}, abstractNote={Skin is the largest human organ with easily noticeable biophysical manifestations of aging. As human tissues age, there is chronological accumulation of biophysical changes due to internal and environmental factors. Skin aging leads to decreased elasticity and the loss of dermal matrix integrity via degradation. The mechanical properties of the dermal matrix are maintained by fibroblasts, which undergo replicative aging and may reach senescence. While the secretory phenotype of senescent fibroblasts is well studied, little is known about changes in the fibroblasts biophysical phenotype. Therefore, we compare biophysical properties of young versus proliferatively aged primary fibroblasts via fluorescence and traction force microscopy, single-cell atomic force spectroscopy, microfluidics, and microrheology of the cytoskeleton. Results show senescent fibroblasts have decreased cytoskeletal tension and myosin II regulatory light chain phosphorylation, in addition to significant loss of traction force. The alteration of cellular forces is harmful to extracellular matrix homeostasis, while decreased cytoskeletal tension can amplify epigenetic changes involved in senescence. Further exploration and detection of these mechanical phenomena provide possibilities for previously unexplored pharmaceutical targets against aging.}, number={34}, journal={Proceedings of the National Academy of Sciences}, author={Rebehn, Lydia and Khalaji, Samira and KleinJan, Fenneke and Kleemann, Anja and Port, Fabian and Paul, Patrick and Huster, Constantin and Nolte, Ulla and Singh, Karmveer and Kwapich, Lisa and Pfeil, Jonas and Pula, Taner and Fischer-Posovszky, Pamela and Scharffetter-Kochanek, Karin and Gottschalk, Kay-E.}, year={2023}, month=aug, pages={e2301880120}, language={en} }
@article{Song_An_Zou_2020, title={Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases}, volume={9}, ISSN={2073-4409}, url={https://www.mdpi.com/2073-4409/9/3/671}, DOI={10.3390/cells9030671}, abstractNote={Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors. Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing. Immune cells can remove senescent cells. Immunaging or impaired innate and adaptive immune responses by senescent cells result in persistent accumulation of various senescent cells. Although senolytics—drugs that selectively remove senescent cells by inducing their apoptosis—are recent hot topics and are making significant research progress, senescence immunotherapies using immune cell-mediated clearance of senescent cells are emerging and promising strategies to fight ageing and multiple chronic diseases. This short review provides an overview of the research progress to date concerning senescent cell-caused chronic diseases and tissue ageing, as well as the regulation of senescence by small-molecule drugs in clinical trials and different roles and regulation of immune cells in the elimination of senescent cells. Mounting evidence indicates that immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan.}, number={3}, journal={Cells}, author={Song, Ping and An, Junqing and Zou, Ming-Hui}, year={2020}, month=mar, pages={671}, language={en} }
