Induction of inverted morphology in brain organoids by vertical-mixing bioreactors

Dang Ngoc Anh Suong, Keiko Imamura, Ikuyo Inoue, Ryotaro Kabai, Satoko Sakamoto, Tatsuya Okumura, Yoshikazu Kato, Takayuki Kondo, Yuichiro Yada, William L. Klein, Akira Watanabe, Haruhisa Inoue*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Article number1213
JournalCommunications Biology
Issue number1
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)


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