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.

Základní údaje

Originální název

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

Autoři

IBRAHIM, Akkouh (garant), Hana HŘÍBKOVÁ (203 Česká republika, domácí), Marta GRABIEC (616 Polsko, domácí), Eva BUDINSKÁ (703 Slovensko, domácí), Attila SZABO, Tomáš KAŠPÁREK (203 Česká republika, domácí), Andreassen A. OLE, Yuh-Man SUN (826 Velká Británie a Severní Irsko, domácí) a Srdjan DJUROVIC

Vydání

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

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30215 Psychiatry

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 6.600

Kód RIV

RIV/00216224:14110/22:00125260

Organizační jednotka

Lékařská fakulta

DOI

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

UT WoS

000746192700022

Klíčová slova anglicky

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

Štítky

14110222, 14110513, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 9. 3. 2023 20:00, Mgr. Michaela Hylsová, Ph.D.

Anotace

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.

Návaznosti

EF15_003/0000469, projekt VaV

Název: Cetocoen Plus

MUNI/A/1418/2021, interní kód MU

Název: Biomedicínské vědy II (Akronym: BIOMED)

Investor: Masarykova univerzita, Biomedicínské vědy II

NV15-31063A, projekt VaV

Název: 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 a 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, roč. 48, č. 1, s. 190-198. ISSN 0586-7614. Dostupné z: 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 a 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, roč.~48, č.~1, s.~190-198. ISSN~0586-7614. Dostupné z: https://dx.doi.org/10.1093/schbul/sbab092.

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