The intestinal epithelium is the fastest self-renewing tissue in the body. Rapid self-renewal is enabled by stem cells that reside at the bottom of highly curved invaginations called crypts. To maintain homeostasis, stem cells constantly divide, giving rise to new cells that proliferate further at the transit amplifying zone, differentiate, and migrate to the tip of finger-like protrusions called villi, where they are extruded into the intestinal lumen. How the distinct functions involved in intestinal self-renewal are coordinated to ensure homeostasis is poorly understood. In this project we will test the hypothesis that the forces experienced by cell nuclei govern cell division, migration and differentiation. We will test this hypothesis using intestinal organoids as model systems. These organoids contain the main cell types of the intestinal epithelium, compartmentalize these cell types into functional units, fold into a crypt-like geometry, and capture essential features of cell proliferation, differentiation, motility and extrusion. By combining novel 2D and 3D culture systems, we will map cellular and nuclear forces with single cell resolution. We will then study the mechanistic relationship between these forces and the cell division rates and migration velocity. By using single cell RNAseq we will study how nuclear mechanotransduction impacts cell differentiation. We expect that this project will unveil a new range of mechanisms by which physical forces govern tissue homeostasis.
1) Perez-Gonzalez et al. Mechanical compartmentalization of the intestinal organoid enables crypt folding and collective cell migration. https://doi.org/10.1101/2020.09.20.299552 (2020)
2) Elosegui-Artola A, et al. Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores. Cell, 30;171(6):1397-1410.e14 (2017).
Job position description
We are looking for PhD students to work on the fundamental understanding of the mechanobiology of intestinal organoids. The student will use a wide range of concepts and methods encompassing the fields of organoid biology, cell mechanics, life microscopy, molecular and cellular biology and microfabrication. The students will contribute to common lab supporting tasks, research collaborations, recording and reporting processes, as well as publications and other scientific communications derived from this work (outreach activities, among others). Applicants should possess a strong background in molecular and cell biology, physics or associated disciplines. Specific experience in the fields of organoid biology and mechanobiology will be an advantage.