Assistant Professor Kyoto University Kyoto, Kyoto, Japan
Abstract: Tissue morphogenesis is one of the emergent phenomena, which is referred to as a property that cannot explained merely as the sum of its components, such as functions of genes and cellular behaviors. Understanding the mechanisms of morphological emergence is essential for accurately predicting or designing tissue shapes in regenerative medicine and tissue engineering. In physics, emergence is defined as a qualitative property that can only occur in the limit that the number of microscopic constituents tends to infinity. Applying this principle to biology requires mathematical descriptions of genetic and cellular behaviors. This supports the need for multicellular in vitro models such as 3D organoids and micropatterning, as they allow the extraction of tissue morphogenesis in a controlled environment. Indeed, the multicellular in vitro models have advanced our understanding of epithelial self-organization, such as eyes and gut. However, mesenchymal tissues like limbs and tails remain poorly understood due to their complex 3D cellular dynamics. To address this, we developed a novel limb organoid system. When we cultured limb mesenchymal cells derived from mouse embryos with Fgf and Wnt, these organoids exhibited symmetry breaking and self-organized digit-like structures, even without directional cues. Agent-based modeling revealed that cell sorting, self-organized morphogen gradient, and cell polarity drive these processes. By applying continuum limits to the equations describing the cellular behaviors in the agent-based model, we derived partial differential equations, showing a type of mathematical instabilities as a potential mechanism explaining the emergence of digit tissue morphologies. Capitalizing on these insights, our objective extends to reconstructing limb morphogenesis using limb mesenchyme derived from human ES cells. Our approach highlights the potential of organoid and mathematical models, paving the way for precision tissue engineering and functional limb regeneration strategies.
Funding Source: Funded by JSPS and ASHBi fusion grant
