Size control and density regulation in living cells – mechanisms and physiological impact of crowding homeostasis
Seminar organized by Matthieu Piel and Gabriel Neurohr from November 24th to 28th, 2025
Participants
Markus BASAN (Harvard University – Boston, Etats-Unis), Marco CONSENTINO LAGOMARSINO (IFOM et Université de Milan – Milan, Italie), Morgan DELARUE (LAAS-CNRS – Toulouse, France), Rachel EDGAR (Imperial College London and the Francis Crick Institut – Londres, Royaume-Uni), Robbie LOEWITH (Université de Genève – Suisse), Teemu MITTIENEN (Massachusetts Institute of Technology – Cambridge, États-Unis), Gabriel NEUROHR (ETH – Zurich, Suisse), Simone REBER (Max Planck Institut for Infection Biology – Berlin, Allemagne), Matthieu PIEL (Institut Curie – Paris, France), Pierre SENS (Institut Curie – Paris, France), Jan SKOTHIEM (Stanford University – Stanford, États-Unis), Larisa VENKOVA (Institut de Biochimie et Génétique Cellulaires, Université de Bordeaux – Bordeaux, France), Karsten WEISS (ETH – Zurich, Suisse).
Résumé

Crédits: Kotryna Vaidziulyte, Institut Curie
Du 24 au 28 novembre 2025, 13 scientifiques – parmi lesquels figurait Larisa Venkova, une jeune chercheuse postdoctorale – se sont réunis pour échanger leurs résultats et approfondir leur compréhension d’un processus fondamental : la croissance cellulaire. Ce mécanisme est essentiel à la reproduction, au développement, au bon fonctionnement et à la santé des organismes vivants, mais il intervient également dans des pathologies comme le cancer.
Les participants, représentant des domaines aussi variés que la physique théorique, la biochimie, la biologie cellulaire et moléculaire ou encore la biophysique, travaillent sur une large gamme d’organismes modèles, allant des bactéries aux cellules de mammifères, en passant par les levures. Le séminaire a porté sur trois dimensions clés de la croissance cellulaire : la régulation de la teneur en eau par l’osmose, qui influence la croissance en volume ; le contrôle de la teneur en macromolécules par la synthèse des protéines, déterminant la croissance en masse sèche ; et enfin la coordination de l’homéostasie, qui assure l’équilibre entre la synthèse des composants, la croissance en volume et le taux de division, afin de maintenir une répartition des tailles et une densité constante au sein des populations cellulaires.
Ces trois éléments constituent ce que l’on appelle les *« lois de la croissance cellulaire »*, un cadre théorique encore incomplet en raison de la diversité des approches et des connaissances impliquées. L’objectif de ce séminaire était d’offrir aux chercheurs l’opportunité d’explorer des aspects moins familiers de leur discipline, d’évaluer la cohérence et l’exhaustivité des théories actuelles, et de progresser vers une théorie unifiée de la croissance cellulaire.
Summary
From November 24 to 28, 2025, 13 scientists—including a young postdoctoral researcher, Larisa Venkova—gathered to share results and discussions aimed at understanding the fundamental process of cellular growth, which lies at the heart of how living organisms reproduce, develop and self-maintain, but also contributes to diseases such as cancer. The participants represented fields such as theoretical physics, biochemistry, cellular and molecular biology, and biophysics across a range of model organisms, from bacteria to mammalian cells, as well as yeasts. The seminar was focusing on three key aspects of cell growth: water content, regulated by osmosis (volume growth); macromolecular content, controlled by protein synthesis (dry mass growth); and the coordinated maintenance (“homeostasis”) of component synthesis, volume growth, and division rate to maintain size distribution and ensure constant density. Together, these elements form the cell ‘growth laws’. These laws remain incomplete, partly due to the diversity of concepts and knowledge involved. The seminar enabled participants to explore in detail the aspects less familiar to them and to examine the compatibility and completeness of existing theories, with the hope of developing a coherent theory of cell growth.
Report
The intracellular milieu is filled with a highly complex fluid with unique features that allow thousands of chemical reactions to occur simultaneously. In recent years it became evident that the physico-chemical properties of the nucleo- and cytoplasm have important roles for cell physiology. In particular the high overall concentration of macromolecules in the cytoplasm gives rise to a crowding effect that affects polymer dynamics, weak molecular interactions and the formation of biomolecular condensates. Despite the apparent importance of cell size and macromolecular density homeostasis, our understanding of these complex processes is still very limited and cell growth laws are still incomplete as they do not form a fully coherent ensemble. Understanding how the production of new biomass is coordinated with the expansion of cell volume to control the crowding and concentrations of the major players and how this is coordinated with proliferation is a multiscale problem that requires interdisciplinary efforts. Progress in this area has long been limited not only by the difficulty to precisely measure the relevant quantities but also by the complex integration of multiple theoretical frameworks. In the last decade, several technological advances have allowed measurements of cell volume, dry mass, and macromolecular composition with unprecedented precision, and integration of theoretical frameworks has been a major effort. A key goal of the seminar was to connect theorists with experimental scientists. Each day of the seminar was started with an introduction into a theory that pointed out important assumptions and blind spots that need experimental testing.
Control of intracellular water content and osmostasis: as cell volume is mostly defined by cellular water content, the osmotic potential of intracellular molecules was discussed extensively. A well-established theoretical concept that explains how cells maintain their volume is the pump-leak model, that describes how cells counteract the passive influx of ions through active ion pumps, as well as the electroneutrality and force balance. A crucial aspect is to know the amount of each cellular soluble component and to which extent they contribute to the water potential, to determine the water content. The amount of counterions for macromolecules appear to be still unclear, as well as the the fraction of these counterions that is osmotically active. The discussions revealed that more accurate methods to measure available intracellular ion concentrations in cells need to be developed to understand this problem. Because in ideal solutions, the osmotic activity is directly proportional to the osmolyte concentration, the contribution of macromolecules has been largely ignored in the past, as they are much less concentrated than ions and metabolites. However, in crowded systems, the osmotic activity of large molecules can be much greater than expected from their concentration alone. How much macromolecules contribute to the osmotic activity inside cells and how condensation of macromolecules influences this activity has been extensively discussed. Direct evidence that macromolecules can influence osmotic equilibria inside cells was presented, indicating that macromolecules play a role – especially to dictate the nucleoplasmic density. Yet it is still unclear to what extent they contribute to the overall water content of a cell. It became clear that the timescales of protein condensation and water transport across membranes play a key role in this process and need to be precisely measured.
Control of macromolecule synthesis and cell growth: The basics of growth laws —frameworks that relate growth rate, macromolecular synthesis, and cellular composition— were exposed and how they can explain scaling of major cellular components as a function of growth rates, in bacteria, yeast and mammalian cells, where the experiments to test the validity of these laws are still incomplete. New quantitative data in yeast were shared to explain the scaling of RNA amount to cell size and the regulation of translation rates in various growth conditions. Growth laws were also explored in various biological contexts such as starvation, senescence and circadian cycles. Finally, a missing element was proposed both from theory and experiments, to integrate growth laws and cell mechanics, at the single cell level (cytoskeleton, cell wall) and within tissues.
Ensuring size and density homeostasis: Growing cells can experience a multitude of perturbations and they possess homeostasis mechanism to fight noisy processes. Processes ensuring that cells grow the same extent in volume and macromolecular content were discussed, from the demonstration of the existence of coupling, to molecular biology of density (mTORC1) and surface tension (mTORC2) sensing. Methods to access measures of dry mass density were exposed, including size measures over a large number of generations, with single cell linage tracing. The impact of cytoplasmic density was also discussed in details, including the notion of crowding and its impact on growth and nuclear state (nuclear crowding and volume), including a variety of contexts such as energy depletion, heat shock, osmotic shocks. The last session was a free discussion to extract major challenges and open questions, such as questioning the notion of ‘excluded volume’ in Ponder plots, the amount of glutamate versus potassium in cells, the osmotic potential of ribosomes and the origin of growth rate fluctuations.
OpenEdition vous propose de citer ce billet de la manière suivante :
ldiebold (10 février 2026). Size control and density regulation in living cells – mechanisms and physiological impact of crowding homeostasis. Les carnets de la Fondation des Treilles. Consulté le 9 mars 2026 à l’adresse https://doi.org/10.58079/15no9

