TFZN · Understanding the mechanisms that govern organ morphostasis and repair

Understanding the mechanisms that govern organ morphostasis and repair

Understanding organogenesis, organ morphostasis and regeneration is crucial to many areas of biology and medicine, including the generation of “organs-on-a-chip” and controlled in vitro organ engineering for clinical applications. As life expectancy around the world rises, knowledge on organ formation and regeneration is becoming crucial to treat diseases of old age. This work focused on understanding how tissue patterning and proportions are recovered after damage by the collective behavior of cells interacting simultaneously. For this, the individual researcher used the neuromasts of the superficial lateral line in zebrafish as an optimal experimental system to understand organ regeneration. These small mechanosensory organs enable fishes and amphibians to sense water displacement around their bodies. Neuromasts are formed by a circular pseudo-stratified epithelium of about 70 cells that are classified in three main cell types: mantle cells, sustentacular cells and hair-cells. Mantle cells form an outer rim of the neuromast epithelium. Inner sustentacular cells comprise the majority of cells and behave as stem cells. Cilliated hair-cells are the mechanosensory elements, and are located in the center of the organ. Neuromast hair cells are homologous to those found in the mammalian inner ear. When fish hair cells are lost due to chemical or mechanical damage, they regenerate an unlimited number of times. By stark contrast, the mammalian ear does not have this capacity. This means that, as we age, hair cells are lost to environmental insults such as loud noises, some medications and certain health conditions. We cannot recover them. People in old age, therefore, suffer disproportionately from hearing loss and tinnitus (ear ringing). In addition, hair cells in the vestibular system that sense acceleration and gravity are critical for balance. Deficits in this system can cause nausea and falls that can be catastrophic for people. The scientific objective of this action is to gain understanding of the process of organ patterning during development or regeneration. We have studied the neuromasts of the zebrafish lateral line as a model to disentangle general principles of organogenesis as well as a model of the inner ear in particular. We narrowed down a list of candidate genes which we then studied in the neuromast by expression and loss-of-function analysis. We then studied how mutations in a subset of genes in the wnt or notch pathways affect the spatial organization of cells within the organ. To achieve it, we used live spinning-disk microscopy. We analyzed the resulting image data with machine learning techniques that allow us to extract a digital representations of the cells in order to compare it with computational models. Mutations in organogenesis usually result in broad defects in morphology of organs. The processes we have studied, however, are more subtle. We have focused on cell orientation relative to each other, changes in cell-cell contact and their interplay with the cell shape and migration. Because this is seldom studied, specially in the context of a live vertebrate, this work contributes to answer how collectives of cells organize themselves to fulfill all the intricate functions of our body.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз