Nonomura, M. | bioRxiv Science

bioRxiv2024

Predicting Organoid Morphology Through a Phase Field Model: Insights into Cell Division and Lumenal Pressure

Organoids are ideal systems to predict the phenotypes of organs. However, there is currently a lack of understanding regarding the generalized rules that enable use of simple cellular principles to make morphological predictions of entire organoids. Therefore, we employed a phase field model with the following basic components: the minimum conditions for the timing and volume of cell division, lumen nucleation rules, and lumenal pressure. Through our model, we could compute and generate a myriad of organoid phenotypes observed till date. We propose morphological indices necessary to characterize the shapes and construct phase diagrams and show their dependencies on proliferation time and lumen pressure. Additionally, we introduced the lumen-index parameter, which helped in examining the criteria to maintain organoids as spherical structures comprising a single layer of cells and enclosing an intact lumen. Finally, we predict a star-like organoid phenotype that did not undergo differentiation, suggesting that the volume constraint during cell division may determine the final phenotype. In summary, our approach provides researchers with guidelines to test the mechanisms of self-organization and predict the shape of organoid. Author summaryIn nature, a wide variety of organ morphologies are observed. Owing to the complexity of the process underlying the acquisition of organs morphology, it is challenging to investigate the mechanisms that lead to such variations. A promising approach to study these variations is the use of "computational organoid" study, which is the computational-based study of self-organizing shapes in multicellular assemblies and fluid-filled cavities called lumens that develop from a few proliferating cells. This study explores general mechanisms that dictate how various mechanical factors affect the growing self-organized multicellular assembly. We relied on computer simulations of the mathematical model called multicellular phase-field model with lumens and explored the mechanical factor effects, such as the lumen pressure while considering the time and volume conditions required for cell division. These simulations generated and categorized a wide range of organoid phenotypes based on the varying lumen pressure and cell division conditions. These phenotypes were characterized into seven distinct classes, based on the morphological index sets, including a cellular monolayer/multilayer surrounding single or multiple lumens and branch formation. These phenotypes were obtained without the assumption of differentiation. Our study elucidates the mechanisms underlying the organoid and organ formation with different shapes, thereby highlighting the significance of mechanical forces in shaping these complex biological structures.

cell biology↗

bioRxiv2024

Generic rules of lumen nucleation and fusion in epithelial organoids

Many internal organs in the body harbor a fluid-filled lumen. The mechanisms of lumens initiation and fusion have been reported as dependent on organ-type during organogenesis. In contrast, the physics of lumen suggests that force balance between luminal pressure and cell mechanics could lead to conserved rules which may unify their self-organisation. However, this hypothesis lacks experimental evidence. Here we compare lumen dynamics for three different systems (MDCK cysts, pancreatic spheres, and epiblast cysts) by using quantitative cell biology, microfabrication and theory. We report that initial cell number determines the maximum number of lumens but does not impact the steady state which is a final single lumen. In addition, lumen numbers exhibit two phases over time, a nucleation phase followed by a fusion phase. In the nucleation phase, lumens form between two cells in pancreatic and MDCK cysts whereas they form at the rosette stage between ten cells in epiblasts. In the second phase, lumens fuse by an increase in lumen volume for pancreatic spheres and MDCK cysts, whereas cell convergent directional motion leads to lumens fusion in epiblasts. We show that these phenomena are associated to the luminal hydrostatic pressure. We support these results with theoretical arguments and numerical simulations. We finally use MDCK cysts to manipulate cell adhesion and lumen volume and we successfully reproduce the fusion dynamics of pancreatic spheres and epiblasts. Our results reveal self-organisation rules of lumens across systems with relevance for morphogenesis during development and for the design of synthetic organs.

biophysics↗

bioRxiv2023

The interplay between lumen pressure and cell proliferation determines organoid morphology in a multicellular phase field model

Organoids are ideal systems to predict the phenotypes of organs. However, there is currently a lack of understanding regarding the generalized rules that enable use of simple cellular principles to make morphological predictions of entire organoids. Therefore, we employed a phase field model with the following basic components: the minimum conditions for the timing and volume of cell division, lumen nucleation rules, and lumenal pressure. Through our model, we could compute and generate a myriad of organoid phenotypes observed till date. We propose morphological indices necessary to characterize the shapes and construct phase diagrams and show their dependencies on proliferation time and lumen pressure. Additionally, we introduced the lumen-index parameter, which helped in examining the criteria to maintain organoids as spherical structures comprising a single layer of cells and enclosing an intact lumen. Finally, we predict a star-like organoid phenotype that did not undergo differentiation, suggesting that the volume constraint during cell division may determine the final phenotype. In summary, our approach provides researchers with guidelines to test the mechanisms of self-organization and predict the shape of organoid. Author summaryIn nature, a wide variety of organ morphologies are observed. Owing to the complexity of the process underlying the acquisition of organs morphology, it is challenging to investigate the mechanisms that lead to such variations. A promising approach to study these variations is the use of "computational organoid" study, which is the computational-based study of self-organizing shapes in multicellular assemblies and fluid-filled cavities called lumens that develop from a few proliferating cells. This study explores general mechanisms that dictate how various mechanical factors affect the growing self-organized multicellular assembly. We relied on computer simulations of the mathematical model called multicellular phase-field model with lumens and explored the mechanical factor effects, such as the lumen pressure while considering the time and volume conditions required for cell division. These simulations generated and categorized a wide range of organoid phenotypes based on the varying lumen pressure and cell division conditions. These phenotypes were characterized into seven distinct classes, based on the morphological index sets, including a cellular monolayer/multilayer surrounding single or multiple lumens and branch formation. These phenotypes were obtained without the assumption of differentiation. Our study elucidates the mechanisms underlying the organoid and organ formation with different shapes, thereby highlighting the significance of mechanical forces in shaping these complex biological structures.

systems biology↗