TY - JOUR
T1 - Transcriptomic and morphological maturation of human astrocytes in cerebral organoids
AU - Verkerke, Marloes
AU - Berdenis van Berlekom, Amber
AU - Donega, Vanessa
AU - Vonk, Daniëlle
AU - Sluijs, Jacqueline A
AU - Butt, Nayab F
AU - Kistemaker, Lois
AU - de Witte, Lot D
AU - Pasterkamp, R Jeroen
AU - Middeldorp, Jinte
AU - Hol, Elly M
N1 - Funding Information: This work was supported by the Dutch Research Council (NWO) Graduate Program (022.006.001) (MV) and by the NWO Gravitation Program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (024.004.012) (EMH). Publisher Copyright: © 2023 The Authors. GLIA published by Wiley Periodicals LLC.
PY - 2024/2
Y1 - 2024/2
N2 - Cerebral organoids (CerOrgs) derived from human induced pluripotent stem cells (iPSCs) are a valuable tool to study human astrocytes and their interaction with neurons and microglia. The timeline of astrocyte development and maturation in this model is currently unknown and this limits the value and applicability of the model. Therefore, we generated CerOrgs from three healthy individuals and assessed astrocyte maturation after 5, 11, 19, and 37 weeks in culture. At these four time points, the astrocyte lineage was isolated based on the expression of integrin subunit alpha 6 (ITGA6). Based on the transcriptome of the isolated ITGA6-positive cells, astrocyte development started between 5 and 11 weeks in culture and astrocyte maturation commenced after 11 weeks in culture. After 19 weeks in culture, the ITGA6-positive astrocytes had the highest expression of human mature astrocyte genes, and the predicted functional properties were related to brain homeostasis. After 37 weeks in culture, a subpopulation of ITGA6-negative astrocytes appeared, highlighting the heterogeneity within the astrocytes. The morphology shifted from an elongated progenitor-like morphology to the typical bushy astrocyte morphology. Based on the morphological properties, predicted functional properties, and the similarities with the human mature astrocyte transcriptome, we concluded that ITGA6-positive astrocytes have developed optimally in 19-week-old CerOrgs.
AB - Cerebral organoids (CerOrgs) derived from human induced pluripotent stem cells (iPSCs) are a valuable tool to study human astrocytes and their interaction with neurons and microglia. The timeline of astrocyte development and maturation in this model is currently unknown and this limits the value and applicability of the model. Therefore, we generated CerOrgs from three healthy individuals and assessed astrocyte maturation after 5, 11, 19, and 37 weeks in culture. At these four time points, the astrocyte lineage was isolated based on the expression of integrin subunit alpha 6 (ITGA6). Based on the transcriptome of the isolated ITGA6-positive cells, astrocyte development started between 5 and 11 weeks in culture and astrocyte maturation commenced after 11 weeks in culture. After 19 weeks in culture, the ITGA6-positive astrocytes had the highest expression of human mature astrocyte genes, and the predicted functional properties were related to brain homeostasis. After 37 weeks in culture, a subpopulation of ITGA6-negative astrocytes appeared, highlighting the heterogeneity within the astrocytes. The morphology shifted from an elongated progenitor-like morphology to the typical bushy astrocyte morphology. Based on the morphological properties, predicted functional properties, and the similarities with the human mature astrocyte transcriptome, we concluded that ITGA6-positive astrocytes have developed optimally in 19-week-old CerOrgs.
KW - ITGA6
KW - astrocyte
KW - cerebral organoid
KW - iPSC
UR - http://www.scopus.com/inward/record.url?scp=85174320765&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/glia.24479
DO - https://doi.org/10.1002/glia.24479
M3 - Article
C2 - 37846809
SN - 0894-1491
VL - 72
SP - 362
EP - 374
JO - GLIA
JF - GLIA
IS - 2
ER -