---
_id: '6995'
abstract:
- lang: eng
text: Human brain organoids represent a powerful tool for the study of human neurological
diseases particularly those that impact brain growth and structure. However, many
neurological diseases lack obvious anatomical abnormalities, yet significantly
impact neural network functions, raising the question of whether organoids possess
sufficient neural network architecture and complexity to model these conditions.
Here, we explore the network level functions of brain organoids using calcium
sensor imaging and extracellular recording approaches that together reveal the
existence of complex oscillatory network behaviors reminiscent of intact brain
preparations. We further demonstrate strikingly abnormal epileptiform network
activity in organoids derived from a Rett Syndrome patient despite only modest
anatomical differences from isogenically matched controls, and rescue with an
unconventional neuromodulatory drug Pifithrin-α. Together, these findings provide
an essential foundation for the utilization of human brain organoids to study
intact and disordered human brain network formation and illustrate their utility
in therapeutic discovery.
acknowledgement: We thank S. Butler, T. Carmichael and members of the laboratory of
B.G.N. for helpful discussions and comments on the manuscript; N. Vishlaghi and
F. Turcios-Hernandez for technical assistance, and J. Lee, S.-K. Lee, H. Shinagawa
and K. Yoshikawa for valuable reagents. We also thank the UCLA Eli and Edythe Broad
Stem Cell Research Center (BSCRC) and Intellectual and Developmental Disabilities
Research Center microscopy cores for access to imaging facilities. This work was
supported by grants from the California Institute for Regenerative Medicine (CIRM)
(DISC1-08819 to B.G.N.), the National Institute of Health (R01NS089817, R01DA051897
and P50HD103557 to B.G.N.; K08NS119747 to R.A.S.; K99HD096105 to M.W.; R01MH123922,
R01MH121521 and P50HD103557 to M.J.G.; R01GM099134 to K.P.; R01NS103788 to W.E.L.;
R01NS088571 to J.M.P.; R01NS030549 and R01AG050474 to I.M.), and research awards
from the UCLA Jonsson Comprehensive Cancer Center and BSCRC Ablon Scholars Program
(to B.G.N.), the BSCRC Innovation Program (to B.G.N., K.P. and W.E.L.), the UCLA
BSCRC Steffy Brain Aging Research Fund (to B.G.N. and W.E.L.) and the UCLA Clinical
and Translational Science Institute (to B.G.N.), Paul Allen Family Foundation Frontiers
Group (to K.P. and W.E.L.), the March of Dimes Foundation (to W.E.L.) and the Simons
Foundation Autism Research Initiative Bridge to Independence Program (to R.A.S.
and M.J.G.). R.A.S. was also supported by the UCLA/NINDS Translational Neuroscience
Training Grant (R25NS065723), a Research and Training Fellowship from the American
Epilepsy Society, a Taking Flight Award from CURE Epilepsy and a Clinician Scientist
training award from the UCLA BSCRC. J.E.B. was supported by the UCLA BSCRC Rose
Hills Foundation Graduate Scholarship Training Program. M.W. was supported by postdoctoral
training awards provided by the UCLA BSCRC and the Uehara Memorial Foundation. O.A.M.
and A.K. were supported in part by the UCLA-California State University Northridge
CIRM-Bridges training program (EDUC2-08411). We also acknowledge the support of
the IDDRC Cells, Circuits and Systems Analysis, Microscopy and Genetics and Genomics
Cores of the Semel Institute of Neuroscience at UCLA, which are supported by the
NICHD (U54HD087101 and P50HD10355701). We lastly acknowledge support from a Quantitative
and Computational Biosciences Collaboratory Postdoctoral Fellowship to S.M. and
the Quantitative and Computational Biosciences Collaboratory community, directed
by M. Pellegrini.
alternative_title:
- Nature Neuroscience
article_processing_charge: Yes
author:
- first_name: Ranmal A.
full_name: Samarasinghe, Ranmal A.
last_name: Samarasinghe
- first_name: Osvaldo
full_name: Miranda, Osvaldo
id: 862A3C56-A8BF-11E9-B4FA-D9E3E5697425
last_name: Miranda
orcid: 0000-0001-6618-6889
- first_name: Jessie E.
full_name: Buth, Jessie E.
last_name: Buth
- first_name: Simon
full_name: Mitchell, Simon
last_name: Mitchell
- first_name: Isabella
full_name: Ferando, Isabella
last_name: Ferando
- first_name: Momoko
full_name: Watanabe, Momoko
last_name: Watanabe
- first_name: Arinnae
full_name: Kurdian, Arinnae
last_name: Kurdian
- first_name: Peyman
full_name: Golshani, Peyman
last_name: Golshani
- first_name: Kathrin
full_name: Plath, Kathrin
last_name: Plath
- first_name: William E.
full_name: Lowry, William E.
last_name: Lowry
- first_name: Jack M.
full_name: Parent, Jack M.
last_name: Parent
- first_name: Istvan
full_name: Mody, Istvan
last_name: Mody
- first_name: Bennett G.
full_name: Novitch, Bennett G.
last_name: Novitch
citation:
ama: Samarasinghe RA, Miranda O, Buth JE, et al. Identification of Neural Oscillations
and Epileptiform Changes in Human Brain Organoids. Vol 24. Springer Nature;
2021. doi:10.1038/s41593-021-00906-5
apa: Samarasinghe, R. A., Miranda, O., Buth, J. E., Mitchell, S., Ferando, I., Watanabe,
M., … Novitch, B. G. (2021). Identification of neural oscillations and epileptiform
changes in human brain organoids (Vol. 24). Springer Nature. https://doi.org/10.1038/s41593-021-00906-5
chicago: Samarasinghe, Ranmal A., Osvaldo Miranda, Jessie E. Buth, Simon Mitchell,
Isabella Ferando, Momoko Watanabe, Arinnae Kurdian, et al. Identification of
Neural Oscillations and Epileptiform Changes in Human Brain Organoids. Vol.
24. Springer Nature, 2021. https://doi.org/10.1038/s41593-021-00906-5.
ieee: R. A. Samarasinghe et al., Identification of neural oscillations
and epileptiform changes in human brain organoids, vol. 24. Springer Nature,
2021.
ista: Samarasinghe RA, Miranda O, Buth JE, Mitchell S, Ferando I, Watanabe M, Kurdian
A, Golshani P, Plath K, Lowry WE, Parent JM, Mody I, Novitch BG. 2021. Identification
of neural oscillations and epileptiform changes in human brain organoids, Springer
Nature, 32p.
mla: Samarasinghe, Ranmal A., et al. Identification of Neural Oscillations and
Epileptiform Changes in Human Brain Organoids. Vol. 24, Springer Nature, 2021,
doi:10.1038/s41593-021-00906-5.
short: R.A. Samarasinghe, O. Miranda, J.E. Buth, S. Mitchell, I. Ferando, M. Watanabe,
A. Kurdian, P. Golshani, K. Plath, W.E. Lowry, J.M. Parent, I. Mody, B.G. Novitch,
Identification of Neural Oscillations and Epileptiform Changes in Human Brain
Organoids, Springer Nature, 2021.
date_created: 2019-11-10T11:23:58Z
date_published: 2021-08-23T00:00:00Z
date_updated: 2023-08-04T10:49:44Z
day: '23'
department:
- _id: GradSch
- _id: SiHi
doi: 10.1038/s41593-021-00906-5
external_id:
isi:
- '000687516300001'
pmid:
- '34426698 '
intvolume: ' 24'
isi: 1
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1038/s41593-021-00906-5
month: '08'
oa: 1
oa_version: Published Version
page: '32'
pmid: 1
publication_identifier:
eissn:
- 1546-1726
issn:
- 1097-6256
publication_status: published
publisher: Springer Nature
status: public
title: Identification of neural oscillations and epileptiform changes in human brain
organoids
type: technical_report
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 24
year: '2021'
...
---
_id: '7358'
abstract:
- lang: eng
text: Telencephalic organoids generated from human pluripotent stem cells (hPSCs)
are emerging as an effective system to study the distinct features of the developing
human brain and the underlying causes of many neurological disorders. While progress
in organoid technology has been steadily advancing, many challenges remain including
rampant batch-to-batch and cell line-to-cell line variability and irreproducibility.
Here, we demonstrate that a major contributor to successful cortical organoid
production is the manner in which hPSCs are maintained prior to differentiation.
Optimal results were achieved using fibroblast-feeder-supported hPSCs compared
to feeder-independent cells, related to differences in their transcriptomic states.
Feeder-supported hPSCs display elevated activation of diverse TGFβ superfamily
signaling pathways and increased expression of genes associated with naïve pluripotency.
We further identify combinations of TGFβ-related growth factors that are necessary
and together sufficient to impart broad telencephalic organoid competency to feeder-free
hPSCs and enable reproducible formation of brain structures suitable for disease
modeling.
article_processing_charge: No
author:
- first_name: Momoko
full_name: Watanabe, Momoko
last_name: Watanabe
- first_name: Jillian R.
full_name: Haney, Jillian R.
last_name: Haney
- first_name: Neda
full_name: Vishlaghi, Neda
last_name: Vishlaghi
- first_name: Felix
full_name: Turcios, Felix
last_name: Turcios
- first_name: Jessie E.
full_name: Buth, Jessie E.
last_name: Buth
- first_name: Wen
full_name: Gu, Wen
last_name: Gu
- first_name: Amanda J.
full_name: Collier, Amanda J.
last_name: Collier
- first_name: Osvaldo
full_name: Miranda, Osvaldo
id: 862A3C56-A8BF-11E9-B4FA-D9E3E5697425
last_name: Miranda
orcid: 0000-0001-6618-6889
- first_name: Di
full_name: Chen, Di
last_name: Chen
- first_name: Shan
full_name: Sabri, Shan
last_name: Sabri
- first_name: Amander T.
full_name: Clark, Amander T.
last_name: Clark
- first_name: Kathrin
full_name: Plath, Kathrin
last_name: Plath
- first_name: Heather R.
full_name: Christofk, Heather R.
last_name: Christofk
- first_name: Michael J.
full_name: Gandal, Michael J.
last_name: Gandal
- first_name: Bennett G.
full_name: Novitch, Bennett G.
last_name: Novitch
citation:
ama: Watanabe M, Haney JR, Vishlaghi N, et al. TGFβ superfamily signaling regulates
the state of human stem cell pluripotency and competency to create telencephalic
organoids. bioRxiv. 2019. doi:10.1101/2019.12.13.875773
apa: Watanabe, M., Haney, J. R., Vishlaghi, N., Turcios, F., Buth, J. E., Gu, W.,
… Novitch, B. G. (2019). TGFβ superfamily signaling regulates the state of human
stem cell pluripotency and competency to create telencephalic organoids. bioRxiv.
Cold Spring Harbor Laboratory. https://doi.org/10.1101/2019.12.13.875773
chicago: Watanabe, Momoko, Jillian R. Haney, Neda Vishlaghi, Felix Turcios, Jessie
E. Buth, Wen Gu, Amanda J. Collier, et al. “TGFβ Superfamily Signaling Regulates
the State of Human Stem Cell Pluripotency and Competency to Create Telencephalic
Organoids.” BioRxiv. Cold Spring Harbor Laboratory, 2019. https://doi.org/10.1101/2019.12.13.875773.
ieee: M. Watanabe et al., “TGFβ superfamily signaling regulates the state
of human stem cell pluripotency and competency to create telencephalic organoids,”
bioRxiv. Cold Spring Harbor Laboratory, 2019.
ista: Watanabe M, Haney JR, Vishlaghi N, Turcios F, Buth JE, Gu W, Collier AJ, Miranda
O, Chen D, Sabri S, Clark AT, Plath K, Christofk HR, Gandal MJ, Novitch BG. 2019.
TGFβ superfamily signaling regulates the state of human stem cell pluripotency
and competency to create telencephalic organoids. bioRxiv, 10.1101/2019.12.13.875773.
mla: Watanabe, Momoko, et al. “TGFβ Superfamily Signaling Regulates the State of
Human Stem Cell Pluripotency and Competency to Create Telencephalic Organoids.”
BioRxiv, Cold Spring Harbor Laboratory, 2019, doi:10.1101/2019.12.13.875773.
short: M. Watanabe, J.R. Haney, N. Vishlaghi, F. Turcios, J.E. Buth, W. Gu, A.J.
Collier, O. Miranda, D. Chen, S. Sabri, A.T. Clark, K. Plath, H.R. Christofk,
M.J. Gandal, B.G. Novitch, BioRxiv (2019).
date_created: 2020-01-23T09:53:40Z
date_published: 2019-12-13T00:00:00Z
date_updated: 2022-06-17T08:03:32Z
day: '13'
doi: 10.1101/2019.12.13.875773
extern: '1'
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1101/2019.12.13.875773
month: '12'
oa: 1
oa_version: Preprint
page: '75'
publication: bioRxiv
publication_status: published
publisher: Cold Spring Harbor Laboratory
status: public
title: TGFβ superfamily signaling regulates the state of human stem cell pluripotency
and competency to create telencephalic organoids
type: preprint
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2019'
...