Derivation and Molecular Characterization of a Morphological
Subpopulation of Human iPSC Astrocytes Reveal a Potential Role
in Schizophrenia and Clozapine Response

J 2022

Derivation and Molecular Characterization of a Morphological Subpopulation of Human iPSC Astrocytes Reveal a Potential Role in Schizophrenia and Clozapine Response

IBRAHIM, Akkouh, Hana HŘÍBKOVÁ, Marta GRABIEC, Eva BUDINSKÁ, Attila SZABO et. al.

Basic information

Original name

Derivation and Molecular Characterization of a Morphological Subpopulation of Human iPSC Astrocytes Reveal a Potential Role in Schizophrenia and Clozapine Response

Authors

IBRAHIM, Akkouh (guarantor), Hana HŘÍBKOVÁ (203 Czech Republic, belonging to the institution), Marta GRABIEC (616 Poland, belonging to the institution), Eva BUDINSKÁ (703 Slovakia, belonging to the institution), Attila SZABO, Tomáš KAŠPÁREK (203 Czech Republic, belonging to the institution), Andreassen A. OLE, Yuh-Man SUN (826 United Kingdom of Great Britain and Northern Ireland, belonging to the institution) and Srdjan DJUROVIC

Edition

SCHIZOPHRENIA BULLETIN, Oxford, Oxford University Press, 2022, 0586-7614

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30215 Psychiatry

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 6.600

RIV identification code

RIV/00216224:14110/22:00125260

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1093/schbul/sbab092

UT WoS

000746192700022

Keywords in English

hiPSC; astrocyte diversity; transcription; glutamate; d-serine

Abstract

V originále

Astrocytes are the most abundant cell type in the human brain and are important regulators of several critical cellular functions, including synaptic transmission. Although astrocytes are known to play a central role in the etiology and pathophysiology of schizophrenia, little is known about their potential involvement in clinical response to the antipsychotic clozapine. Moreover, astrocytes display a remarkable degree of morphological diversity, but the potential contribution of astrocytic subtypes to disease biology and drug response has received little attention. Here, we used state-of-the-art human induced pluripotent stem cell (hiPSC) technology to derive a morphological subtype of astrocytes from healthy individuals and individuals with schizophrenia, including responders and nonresponders to clozapine. Using functional assays and transcriptional profiling, we identified a distinct gene expression signature highly specific to schizophrenia as shown by disease association analysis of more than 10 000 diseases. We further found reduced levels of both glutamate and the NMDA receptor coagonist D-serine in subtype astrocytes derived from schizophrenia patients, and that exposure to clozapine only rescued this deficiency in cells from clozapine responders, providing further evidence that D-serine in particular, and NMDA receptor-mediated glutamatergic neurotransmission in general, could play an important role in disease pathophysiology and clozapine action. Our study represents a first attempt to explore the potential contribution of astrocyte diversity to schizophrenia pathophysiology using a human cellular model. Our findings suggest that specialized subtypes of astrocytes could be important modulators of disease pathophysiology and clinical drug response, and warrant further investigations.

Links

EF15_003/0000469, research and development project

Name: Cetocoen Plus

MUNI/A/1418/2021, interní kód MU

Name: Biomedicínské vědy II (Acronym: BIOMED)

Investor: Masaryk University

NV15-31063A, research and development project

Name: Buněčné markery vedoucí ke specifické léčbě "na míru" schizofrenním pacientům

Citovat

IBRAHIM, Akkouh, Hana HŘÍBKOVÁ, Marta GRABIEC, Eva BUDINSKÁ, Attila SZABO, Tomáš KAŠPÁREK, Andreassen A. OLE, Yuh-Man SUN and Srdjan DJUROVIC. Derivation and Molecular Characterization of a Morphological Subpopulation of Human iPSC Astrocytes Reveal a Potential Role in Schizophrenia and Clozapine Response. SCHIZOPHRENIA BULLETIN. Oxford: Oxford University Press, 2022, vol. 48, No 1, p. 190-198. ISSN 0586-7614. Available from: https://dx.doi.org/10.1093/schbul/sbab092.

@article{1826918,
   author = {Ibrahim, Akkouh and Hříbková, Hana and Grabiec, Marta and Budinská, Eva and Szabo, Attila and Kašpárek, Tomáš and Ole, Andreassen A. and Sun, YuhandMan and Djurovic, Srdjan},
   article_location = {Oxford},
   article_number = {1},
   doi = {http://dx.doi.org/10.1093/schbul/sbab092},
   keywords = {hiPSC; astrocyte diversity; transcription; glutamate; d-serine},
   language = {eng},
   issn = {0586-7614},
   journal = {SCHIZOPHRENIA BULLETIN},
   title = {Derivation and Molecular Characterization of a Morphological Subpopulation of Human iPSC Astrocytes Reveal a Potential Role in Schizophrenia and Clozapine Response},
   url = {https://academic.oup.com/schizophreniabulletin/article/48/1/190/6343183},
   volume = {48},
   year = {2022}
}

TY  - JOUR
ID  - 1826918
AU  - Ibrahim, Akkouh - Hříbková, Hana - Grabiec, Marta - Budinská, Eva - Szabo, Attila - Kašpárek, Tomáš - Ole, Andreassen A. - Sun, Yuh-Man - Djurovic, Srdjan
PY  - 2022
TI  - Derivation and Molecular Characterization of a Morphological Subpopulation of Human iPSC Astrocytes Reveal a Potential Role in Schizophrenia and Clozapine Response
JF  - SCHIZOPHRENIA BULLETIN
VL  - 48
IS  - 1
SP  - 190-198
EP  - 190-198
PB  - Oxford University Press
SN  - 05867614
KW  - hiPSC
KW  - astrocyte diversity
KW  - transcription
KW  - glutamate
KW  - d-serine
UR  - https://academic.oup.com/schizophreniabulletin/article/48/1/190/6343183
N2  - Astrocytes are the most abundant cell type in the human brain and are important regulators of several critical cellular functions, including synaptic transmission. Although astrocytes are known to play a central role in the etiology and pathophysiology of schizophrenia, little is known about their potential involvement in clinical response to the antipsychotic clozapine. Moreover, astrocytes display a remarkable degree of morphological diversity, but the potential contribution of astrocytic subtypes to disease biology and drug response has received little attention. Here, we used state-of-the-art human induced pluripotent stem cell (hiPSC) technology to derive a morphological subtype of astrocytes from healthy individuals and individuals with schizophrenia, including responders and nonresponders to clozapine. Using functional assays and transcriptional profiling, we identified a distinct gene expression signature highly specific to schizophrenia as shown by disease association analysis of more than 10 000 diseases. We further found reduced levels of both glutamate and the NMDA receptor coagonist D-serine in subtype astrocytes derived from schizophrenia patients, and that exposure to clozapine only rescued this deficiency in cells from clozapine responders, providing further evidence that D-serine in particular, and NMDA receptor-mediated glutamatergic neurotransmission in general, could play an important role in disease pathophysiology and clozapine action. Our study represents a first attempt to explore the potential contribution of astrocyte diversity to schizophrenia pathophysiology using a human cellular model. Our findings suggest that specialized subtypes of astrocytes could be important modulators of disease pathophysiology and clinical drug response, and warrant further investigations.
ER  -

IBRAHIM, Akkouh, Hana HŘÍBKOVÁ, Marta GRABIEC, Eva BUDINSKÁ, Attila SZABO, Tomáš KAŠPÁREK, Andreassen A. OLE, Yuh-Man SUN and Srdjan DJUROVIC. Derivation and Molecular Characterization of a Morphological Subpopulation of Human iPSC Astrocytes Reveal a Potential Role in Schizophrenia and Clozapine Response. \textit{SCHIZOPHRENIA BULLETIN}. Oxford: Oxford University Press, 2022, vol.~48, No~1, p.~190-198. ISSN~0586-7614. Available from: https://dx.doi.org/10.1093/schbul/sbab092.

Detailed Information on Publication Record