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Abstract
Organoid technology provides an opportunity to generate brain-like structures by recapitulating developmental steps in the manner of self-organization. Here we examined the vertical-mixing effect on brain organoid structures using bioreactors and established inverted brain organoids. The organoids generated by vertical mixing showed neurons that migrated from the outer periphery to the inner core of organoids, in contrast to orbital mixing. Computational analysis of flow dynamics clarified that, by comparison with orbital mixing, vertical mixing maintained the high turbulent energy around organoids, and continuously kept inter-organoid distances by dispersing and adding uniform rheological force on organoids. To uncover the mechanisms of the inverted structure, we investigated the direction of primary cilia, a cellular mechanosensor. Primary cilia of neural progenitors by vertical mixing were aligned in a multidirectional manner, and those by orbital mixing in a bidirectional manner. Single-cell RNA sequencing revealed that neurons of inverted brain organoids presented a GABAergic character of the ventral forebrain. These results suggest that controlling fluid dynamics by biomechanical engineering can direct stem cell differentiation of brain organoids, and that inverted brain organoids will be applicable for studying human brain development and disorders in the future.
Dang Ngoc Anh Suong et al find that vertical mixing generates iPSC-derived brain organoids displaying an inverted structure with neurons localising at the centre and neural progenitors at the outside. This study illustrates the influence of fluid mechanics relevant to the direction of primary cilia on stem cell differentiation.
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1 Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033); iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan (GRID:grid.509462.c)
2 Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033); iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan (GRID:grid.509462.c); Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan (GRID:grid.509456.b)
3 Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033); Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan (GRID:grid.509456.b)
4 Graduate School of Medicine, Kyoto University, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033)
5 Mixing Technology Laboratory, SATAKE Chemical Equipment Manufacturing Ltd., Saitama, Japan (GRID:grid.258799.8)
6 Northwestern University, Department of Neurobiology, Evanston, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507)
7 Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033); iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan (GRID:grid.509462.c); Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan (GRID:grid.509456.b); Institute for Advancement of Clinical and Translational Science (iACT), Kyoto University Hospital, Kyoto, Japan (GRID:grid.411217.0) (ISNI:0000 0004 0531 2775)