I am interested in uncovering the guiding principles that help us engineer organs in the dish.
As an ELBE postdoctoral fellow, I work among the groups of Jan Brugues (Max Planck Institute of Molecular Cell Biology and Genetics), Frank Jülicher (Max Planck Institute for the Physics of Complex Systems), and Elly Tanaka (Research Institute of Molecular Pathology) in Dresden and Vienna.
I use stem cells to engineer organ-like structures, or organoids, and study how they change shape and become patterned. I combine quantitative 3D imaging with theoretical models to better understand and predict self-organization.
Previously, I performed my doctoral research in Tim Mitchison's lab at Harvard Medical School, studying how microtubule asters grow to fill millimeter-sized frog eggs.
Morphogenetic control of epithelial topology
During development, sheets of cells bend, split, and fuse to generate the intricate shapes of various organs. While past studies have proposed how cell mechanics induce local shape changes, the statistical properties of lumen topology have not been addressed. By combining 3D tissue reconstitution and theory, I am studying the cell biological and physical conditions that determine whether an epithelium remains connected, or divides into multiple, topologically distinct epithelia. (with Argo Mukherjee, Frank Jülicher group)
Spontaneous emergence of a body axis
How do the different body axes emerge from a fertilized egg to make an animal? Organ reconstitution is a powerful approach to study how a group of cells “pattern themselves” (Ishihara et al. 2018). Using stem cells, I grow neural tube organoids and study how the dorsal-ventral body axis is established in the absence external tissues (Meinhardt et al. 2014, Ishihara et al. 2017). By default, these organoids harbor dorsal identity, but treatment with retinoic acid initiates a self-organizing circuit that results in the localized expression of the ventral marker FoxA2. To study the dynamics of this spontaneous symmetry breaking at single cell resolution, I am applying light sheet microscopy on organoids made from FoxA2-Venus cells. In addition, I am investigating the molecular and physical basis of how FoxA2+ cells communicate with each other. (with Elena Gromberg and Teresa Krammer, Elly Tanaka group)
How does the millimeter frog egg divide?
Physical extremes in biology are interesting. The large cytoplasm of frog eggs is organized by radial arrays of microtubules called asters. Asters grow, interact and position themselves to help the frog egg find its division plane. As a graduate student in Tim Mitchison’s group, I asked how microtubule asters grow rapidly to one millimeter in diameter. By reconstituting asters in frog egg extract and imaging their growth, I found that new microtubules are nucleated at positions far from the centrosome (Ishihara et al., 2014). In collaboration with Kirill Korolev, I constructed a theoretical model of aster growth and tested its prediction by experiments (Ishihara et al., 2016). This led us to reconsider the textbook model and propose that large microtubule asters are a meshwork of short, interacting, self-amplifying microtubules.
More recently, two additional projects have come out from my PhD research – one related to the theory of traveling waves (Ishihara et al., 2020 New J. of Phys.) and one report on the spatial regulation of microtubule depolymerization (Ishihara et al., 2021 Mol. Bio. Cell).
Spatial Variation of Microtubule Depolymerization in Large Asters
Traveling fronts in self-replicating persistent random walks with multiple internal states
Spontaneous symmetry breaking and pattern formation of organoids
Reconstitution of a Patterned Neural Tube from Single Mouse Embryonic Stem Cells
Microtubule nucleation remote from centrosomes may explain how asters span large cells
Spatial organization of cytokinesis signaling reconstituted in a cell-free system