Tissue Mechanics in 3D Human Organoids

The failure rates of clinical trial for CNS disorders are higher compared to other clinical trials, possibly due to the existence of crucial - not yet understood - differences between pre-clinical models (e.g., mouse) and actual human brains. This raises the question: what makes a human brain unique? One potential factor contributing to our cognitive superiority over other primates is our larger brain size relative to body size, known as the encephalisation quotient, which is directly linked to a higher number of brain cells. To understand these size variations, it is essential to examine early brain development. Most studies investigating the uniqueness of the human brain have primarily focused on neurogenesis, neuronal differentiation, and connectome (mapping the functional and structural connections within the brain organoid). However, limited knowledge exists regarding how morphogenesis and tissue architecture may contribute to the fundamental framework of a larger brain.

Recent advancements in generating organoids from induced pluripotent stem cells (iPSCs) have enabled the study of a variety of developmental processes. It can be argued that since organoids develop following intrinsic developmental programmes, the tissue morphology resembles well the architecture of the organ. Relevant for this proposal is the fact that culturing human cerebral organoids provides a valuable 3D model for investigating human brain development. The formation of the human columnar neuroepithelium (NE) is the first step in the development of the brain. Furthermore, to better understand this process and the impact on brain size there will be used human iPSCs-derived cerebral organoids, with special focus on the regulation of columnar cell shape and forces of the NE, an important event as NE cell shape contributes to human brain size. In an interdisciplinary approach, there will be combined bioengineering, cell biophysics and functional genetics to study the biophysical principles governing NE development.