リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

大学・研究所にある論文を検索できる 「Induction of inverted morphology in brain organoids by vertical-mixing bioreactors」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

コピーが完了しました

URLをコピーしました

論文の公開元へ論文の公開元へ
書き出し

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

Suong, Dang Ngoc Anh Imamura, Keiko Inoue, Ikuyo Kabai, Ryotaro Sakamoto, Satoko Okumura, Tatsuya Kato, Yoshikazu Kondo, Takayuki Yada, Yuichiro Klein, William L. Watanabe, Akira Inoue, Haruhisa 京都大学 DOI:10.1038/s42003-021-02719-5

2021

概要

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.

この論文で使われている画像

参考文献

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

12

Lancaster, M. A. et al. Cerebral organoids model human brain development

and microcephaly. Nature 501, 373–379 (2013).

Kadoshima, T. et al. Self-organization of axial polarity, inside-out layer

pattern, and species-specific progenitor dynamics in human ES cell-derived

neocortex. Proc. Natl Acad. Sci. USA 110, 20284–20289 (2013).

Di Lullo, E. & Kriegstein, A. R. The use of brain organoids to investigate

neural development and disease. Nat. Rev. Neurosci. 18, 573–584 (2017).

Pasca, S. P. The rise of three-dimensional human brain cultures. Nature 553,

437–445 (2018).

Trujillo, C. A. et al. Complex oscillatory waves emerging from cortical

organoids model early human brain network development. Cell Stem Cell 25,

558–569 (2019).

Quadrato, G. et al. Cell diversity and network dynamics in photosensitive

human brain organoids. Nature 545, 48–53 (2017).

Camp, J. G. et al. Human cerebral organoids recapitulate gene expression

programs of fetal neocortex development. Proc. Natl Acad. Sci. USA 112,

15672–15677 (2015).

Giandomenico, S. L. et al. Cerebral organoids at the air-liquid interface

generate diverse nerve tracts with functional output. Nat. Neurosci. 22,

669–679 (2019).

Muguruma, K., Nishiyama, A., Kawakami, H., Hashimoto, K. & Sasai, Y. Selforganization of polarized cerebellar tissue in 3D culture of human pluripotent

stem cells. Cell Rep. 10, 537–550 (2015).

Seto, Y. & Eiraku, M. Toward the formation of neural circuits in human brain

organoids. Curr. Opin. Cell Biol. 61, 86–91 (2019).

Takebe, T. & Wells, J. M. Organoids by design. Science 364, 956–959 (2019).

Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474,

179–183 (2011).

Sunyer, R. et al. Collective cell durotaxis emerges from long-range intercellular

force transmission. Science 353, 1157–1161 (2016).

Nerurkar, N. L., Lee, C., Mahadevan, L. & Tabin, C. J. Molecular control of

macroscopic forces drives formation of the vertebrate hindgut. Nature 565,

480–484 (2019).

Ito, Y. et al. Turbulence activates platelet biogenesis to enable clinical scale

ex vivo production. Cell 174, 636–648.e618 (2018).

Dahl-Jensen, S. & Grapin-Botton, A. The physics of organoids: a biophysical

approach to understanding organogenesis. Development 144, 946–951 (2017).

Goto-Silva, L. et al. Computational fluid dynamic analysis of physical forces

playing a role in brain organoid cultures in two different multiplex platforms.

BMC Dev. Biol. 19, 3 (2019).

Montes-Olivas, S., Marucci, L. & Homer, M. Mathematical models of

organoid cultures. Front. Genet. 10, 873 (2019).

Pala, R., Alomari, N. & Nauli, S. M. Primary cilium-dependent

signaling mechanisms. Int. J. Mol. Sci. 18, https://doi.org/10.3390/

ijms18112272 (2017).

Elliott, K. H. & Brugmann, S. A. Sending mixed signals: ciliadependent signaling during development and disease. Dev. Biol. 447, 28–41

(2019).

21. Rallu, M. et al. Dorsoventral patterning is established in the telencephalon of

mutants lacking both Gli3 and Hedgehog signaling. Development 129,

4963–4974 (2002).

22. Gulacsi, A. & Anderson, S. A. Shh maintains Nkx2.1 in the MGE by a Gli3independent mechanism. Cereb. Cortex 16, i89–i95 (2006). Suppl 1.

23. Hasenpusch-Theil, K. & Theil, T. The multifaceted roles of primary cilia in the

development of the cerebral cortex. Front Cell Dev. Biol. 9, 630161 (2021).

24. Xavier, G. M. et al. Hedgehog receptor function during craniofacial

development. Dev. Biol. 415, 198–215 (2016).

25. Nechipurenko, I. V. et al. A conserved role for girdin in basal body positioning

and ciliogenesis. Dev. Cell 38, 493–506 (2016).

26. Matsumoto, M. et al. Dynamic changes in ultrastructure of the primary cilium

in migrating neuroblasts in the postnatal brain. J. Neurosci. 39, 9967–9988

(2019).

27. Wilsch-Bräuninger, M., Peters, J., Paridaen, J. T. & Huttner, W. B. Basolateral

rather than apical primary cilia on neuroepithelial cells committed to

delamination. Development 139, 95–105 (2012).

28. Li, Y. et al. Implications of GABAergic neurotransmission in Alzheimer’s

disease. Front Aging Neurosci. 8, 31 (2016).

29. Kondo, T. et al. Modeling Alzheimer’s disease with iPSCs reveals stress

phenotypes associated with intracellular Abeta and differential drug

responsiveness. Cell Stem Cell 12, 487–496 (2013).

30. Nasu, M. et al. Robust formation and maintenance of continuous stratified

cortical neuroepithelium by laminin-containing matrix in mouse ES cell

culture. PLoS ONE 7, e53024 (2012).

31. Higginbotham, H. et al. Arl13b-regulated cilia activities are essential for

polarized radial glial scaffold formation. Nat. Neurosci. 16, 1000–1007 (2013).

32. Nampe, D., Joshi, R., Keller, K., Zur Nieden, N. I. & Tsutsui, H. Impact of

fluidic agitation on human pluripotent stem cells in stirred suspension culture.

Biotechnol. Bioeng. 114, 2109–2120 (2017).

33. Mercurio, S., Serra, L. & Nicolis, S. K. More than just stem cells: functional

roles of the transcription factor Sox2 in differentiated glia and neurons. Int. J.

Mol. Sci. 20, https://doi.org/10.3390/ijms20184540 (2019).

34. Cavallaro, M. et al. Impaired generation of mature neurons by neural stem

cells from hypomorphic Sox2 mutants. Development 135, 541–557 (2008).

35. Higginbotham, H. et al. Arl13b in primary cilia regulates the migration and

placement of interneurons in the developing cerebral cortex. Dev. Cell 23,

925–938 (2012).

36. Baudoin, J. P. et al. Tangentially migrating neurons assemble a primary cilium that

promotes their reorientation to the cortical plate. Neuron 76, 1108–1122 (2012).

37. Qian, X. et al. Brain-region-specific organoids using mini-bioreactors for

modeling ZIKV exposure. Cell 165, 1238–1254 (2016).

38. Sequerra, E. B., Miyakoshi, L. M., Fróes, M. M., Menezes, J. R. & HedinPereira, C. Generation of glutamatergic neurons from postnatal and adult

subventricular zone with pyramidal-like morphology. Cereb. Cortex 20,

2583–2591 (2010).

39. Lai, T. et al. SOX5 controls the sequential generation of distinct corticofugal

neuron subtypes. Neuron 57, 232–247 (2008).

40. Nikouei, K., Muñoz-Manchado, A. B. & Hjerling-Leffler, J. BCL11B/CTIP2 is

highly expressed in GABAergic interneurons of the mouse somatosensory

cortex. J. Chem. Neuroanat. 71, 1–5 (2016).

41. Takahashi, K. et al. Induction of pluripotent stem cells from adult human

fibroblasts by defined factors. Cell 131, 861–872 (2007).

42. Sutcliffe, M. & Lancaster, M. A. A simple method of generating 3D brain

organoids using standard laboratory equipment. Methods Mol. Biol. 1576,

1–12 (2019).

43. Lambert, M. P. et al. Monoclonal antibodies that target pathological

assemblies of Abeta. J. Neurochem. 100, 23–35 (2007).

Acknowledgements

We would like to express our sincere gratitude to all of our co-workers and collaborators:

Kayoko Tsukita, Takako Enami, and Ayako Nagahashi for their technical support, Mikie

Iijima, Nozomi Kawabata, Tomomi Urai, and Miho Nagata for their valuable administrative support, and Minako Tateno for critical reading of the manuscript. This research

was funded in part by a grant for Core Center for iPS Cell Research of the Research

Center Network for Realization of Regenerative Medicine from AMED (H.I.) and the

Uehara Memorial Foundation (H.I.) and partially supported by the Center of Innovation

Program from MEXT and JST (H.I.).

Author contributions

H.I. conceived the project. DN.AS., K.I., I.I., R.K., S.S., T.O., Y.K., T.K., Y.Y. and A.W.

performed the experiments. W.L.K. provided antibodies. DN.AS., K.I., T.K. and H.I.

wrote the manuscript.

Competing interests

The authors declare no competing interests.

COMMUNICATIONS BIOLOGY | (2021)4:1213 | https://doi.org/10.1038/s42003-021-02719-5 | www.nature.com/commsbio

A Self-archived copy in

Kyoto University Research Information Repository

https://repository.kulib.kyoto-u.ac.jp

COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-021-02719-5

Additional information

Supplementary information The online version contains supplementary material

available at https://doi.org/10.1038/s42003-021-02719-5.

Correspondence and requests for materials should be addressed to Haruhisa Inoue.

Peer review information Communications Biology thanks the anonymous reviewers for

their contribution to the peer review of this work. Primary Handling Editor: Christina

Karlsson Rosenthal. Peer reviewer reports are available.

Reprints and permission information is available at http://www.nature.com/reprints

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in

published maps and institutional affiliations.

ARTICLE

Open Access This article is licensed under a Creative Commons

Attribution 4.0 International License, which permits use, sharing,

adaptation, distribution and reproduction in any medium or format, as long as you give

appropriate credit to the original author(s) and the source, provide a link to the Creative

Commons license, and indicate if changes were made. The images or other third party

material in this article are included in the article’s Creative Commons license, unless

indicated otherwise in a credit line to the material. If material is not included in the

article’s Creative Commons license and your intended use is not permitted by statutory

regulation or exceeds the permitted use, you will need to obtain permission directly from

the copyright holder. To view a copy of this license, visit http://creativecommons.org/

licenses/by/4.0/.

© The Author(s) 2021

COMMUNICATIONS BIOLOGY | (2021)4:1213 | https://doi.org/10.1038/s42003-021-02719-5 | www.nature.com/commsbio

13

...

参考文献をもっと見る

全国の大学の
卒論・修論・学位論文

一発検索!

この論文の関連論文を見る