Collective behaviour is a complex behaviour in which understanding of the individual components in more depth does not necessarily explain the collective behaviour of many individuals. This is reminiscent of Aristotle’s quote: “The whole is more than the sum of its parts”. The unexplainable behaviour is the self-organisation of the system. This self-organisation often creates ordered patterns. In molecular and developmental biology, pattern formation is the mechanism by which initially identical cells in a developing tissue assume different forms and functions in space and time. In the lab we explore the role of self-organisation as fundamental properties of multicellularity. We study cellular mechanisms by which single-cells sense their local environment in a multicellular system driving collective behaviours during developmental and regenerative processes. Finally, we develop technologies that cross scales at the spatial, temporal and functional level to bridge the gap between single-cells and organised tissues.
An important defining step in pattern formation is the moment when initially identical cells in a developing tissue differentiate and lineage segregation is established, and symmetry breaks. Precisely, the symmetry-breaking event occurs when, despite all cells being exposed to a uniform growth-promoting environment, only a fraction becomes activated and differentiates. This process is called symmetry "breaking" because the transitions usually bring the system from a symmetric but disordered and variable state into one or more defined, less variable and asymmetric states (e.g. differentiated states). In the lab we are characterizing the triggering mechanisms of the symmetry-breaking events and how some cells may acquire specific cell fates due to an increased responsiveness to extracellular signals and higher probability of transition.
Intestinal Organoid Development
Intestinal organoids are complex three-dimensional structures that mimic cell type composition and tissue organization of the intestine by recapitulating the self-organizing capacity of cell populations derived from a single stem cell. Crucial in this process is a first symmetry-breaking event, in which only a fraction of identical cells in a symmetrical sphere differentiate into Paneth cells, which in turn generates the stem cell niche and leads to asymmetric structures such as crypts and villi. We recently combined a quantitative imaging approach with single-cell gene expression to characterize the development of intestinal organoids from a single cell, showing that their development follows a regeneration process driven by transient Yap1 activation. In the lab we are interested to further understand how single intestinal stem cells exposed to a uniform growth-promoting environment have the intrinsic ability to generate emergent, self-organized behavior resulting in the formation of complex multicellular asymmetric structures.
Cell-to-cell variability during development
Cell-to-cell variability is an inherent and emergent property of populations of cells. It refers to the phenomenon that no two genetically identical cells behave and look identical. This difference may arise from the inherently stochastic and discrete nature of intracellular biochemical reactions, especially when these reactions involve low numbers of molecules. Generally though, robustness in molecular mechanisms can buffer the intrinsic stochasticity of molecular processes while other factors, such as the cell cycle and the microenvironment, can explain the cellular heterogeneity, especially in eukaryotes. In the laboratory we are interested in exploring the role of cell-to-cell variability in pattern formation during development. Especially, we are interested in determining the extent, sources, and roles of cell heterogeneity in stem cells population.
Gastruloids, Neuronal and Cerebral organoids
In the laboratory we are interested in many different self-organized and coordinated events during development. Embryonic stem cells have the intrinsic capacity to follow developmental trajectories in vitro and to give rise to specialised cell types similar to in vivo embryogenesis. Recent studies have demonstrated that they also have the remarkable ability to self-organise into complex structures, mimicking the morphogenetic changes during embryonic development. Specifically, we use gastruloids, neural tube and cerebral organoids, both from mouse and human embryonic stem cells, to study how the neural fate is induced in a population of cells in a coordinated manner, and how this population property emerges.
The recent development of intestinal organoid technology provides a unique opportunity to quantify morphogenesis and dissect the relationship between morphogenesis and cell fate. Moreover, it allows the determination of the underlying mechano-sensing molecular machineries. In specific in the lab we aim to understand the physical mechanism and the biological influence of morphogenesis in organoid development and to find out how tissue mechanics influences fate-specific genetic networks.
Organoids as disease models
Maintaining tissue homeostasis, via periodical tissue renewal and regenerative processes, requires spatio-temporal coordination of cells to ensure tissue function and integrity. The malfunction of these coordinated behaviours during embryogenesis is the cause of many congenital disorders and their deregulation during adult life in actively proliferating and regenerating tissues, such as the intestine, is the basis of many cancers. In the lab we are interested in building next generation in-vitro disease models that recapitulate the complexity of tissue organisation in health and disease.