Retina Organoid Mechanobiology

ongoing

The retina carries signatures of neuronal diseases which have been linked to mechanical abnormalities, including Glaucoma and Alzheimer’s disease. Yet no biophysical retina model exists due to a cross-disciplinary challenge: While stem cell derived organoids mimic the retina in vitro, organoid research has been limited by large variations in cell and tissue organization. Mechanobiology, in turn, has revealed mechanical signals as essential players in regulating cellular behavior to guide organogenesis. Accordingly, the ball is in the court of physicists and bioengineers to quantify those mechanical signals and shape tissue growth by tailoring the physical interactions of cells with their environment. Finally, the functionality of the retina has to be quantified via neuroscience techniques. This multifaceted challenge has prevented the establishment of the retina organoid as a biophysical model. ROMB introduces a biophysical model for the retina which I will use to model Alzheimer’s disease in vitro. It will be built on 4 cross-disciplinary posts: (i) retina organoids as a physiological in vitro model, (ii) tissue mechanics measurements, (iii) neuronal activity readout and (iv) disease modeling. First, I will reveal the mechanical building plan of retina organoids using ferrofluid droplets as mechanical actuators, hereby opening the field of organoid mechanobiology. In a second step, the organoid’s 3D neuronal function will be recorded using lightsheet microscopy. Mechanical, functional and genetic access will allow me in a final step to detect and manipulate Alzheimer’s disease: using mouse retina organoids with a mutation in the App gene, I will mechanically characterize the formation of those peptide aggregates which are the hallmark of disease onset. ROMB opens the door to engineering functional retinas in vitro. Moreover, it will be uniquely suited to tackle mechanically related neuronal diseases and promises a breakthrough for basic and applied research.