Chronic cortisol differentially impacts stem cell-derived astrocytes from major depressive disorder patients

Abstract

Major depressive disorder (MDD) is a prevalent psychiatric disorder, and exposure to stress is a robust risk factor for MDD. Clinical data and rodent models have indicated the negative impact of chronic exposure to stress-induced hormones like cortisol on brain volume, memory, and cell metabolism. However, the cellular and transcriptomic changes that occur in the brain after prolonged exposure to cortisol are less understood. Furthermore, the astrocyte-specific contribution to cortisol-induced neuropathology remains understudied. Here, we have developed an in vitro model of “chronic stress” using human induced pluripotent stem cell (iPSC)-derived astrocytes treated with cortisol for 7 days. Whole transcriptome sequencing reveals differentially expressed genes (DEGs) uniquely regulated in chronic cortisol compared to acute cortisol treatment. Utilizing this paradigm, we examined the stress response transcriptome of astrocytes generated from MDD patient iPSCs. The MDD-specific DEGs are related to GPCR ligand binding, synaptic signaling, and ion homeostasis. Together, these data highlight the unique role astrocytes play in the central nervous system and present interesting genes for future study into the relationship between chronic stress and MDD.

Generation of inflammation-responsive astrocytes from glial progenitors derived from human pluripotent stem cells

“…FBS can also be completely replaced by 10% Knockout Serum Replacement (Thermo Fisher Scientific, cat. # 10828010) as reported ( Heard et al, 2021 ).…”

In vitro modeling of glucocorticoid mechanisms in stress-related mental disorders: Current challenges and future perspectives

“…Recent developments in the field of CPART make the use of in vitro stress models even more relevant ( Marchetto and Gage, 2012 ), since it allows to investigate GC-induced cellular responses in the context of the genetic background of individuals expressing differential susceptibility to develop SRMDs. Indeed, the identification of unique gene expression signatures and related pathways implicated in stress vulnerability, have been identified in neurons and glia from iPSCs derived from SRMD patients ( Vadodaria et al, 2019a ; Vadodaria et al, 2019b ; Vadodaria et al, 2019c ; Seah et al, 2021 ; Heard et al, 2021 ). These models can also be used to examine the effects of genetic risk variants of SRMDs, e.g., polymorphisms in NR3C1 (the gene coding for GR) ( Peng et al, 2018 ), or differential responses to GC exposure between iPSC-derived neurons from healthy and SRMD patients ( Seah et al, 2021 ; Heard et al, 2021 ).…”

“…Indeed, the identification of unique gene expression signatures and related pathways implicated in stress vulnerability, have been identified in neurons and glia from iPSCs derived from SRMD patients ( Vadodaria et al, 2019a ; Vadodaria et al, 2019b ; Vadodaria et al, 2019c ; Seah et al, 2021 ; Heard et al, 2021 ). These models can also be used to examine the effects of genetic risk variants of SRMDs, e.g., polymorphisms in NR3C1 (the gene coding for GR) ( Peng et al, 2018 ), or differential responses to GC exposure between iPSC-derived neurons from healthy and SRMD patients ( Seah et al, 2021 ; Heard et al, 2021 ). The investigation of the neurobiological effects (at the molecular, cellular, morphological, and physiological levels) of hormones (including cortisol), drugs (incl.…”

“…Moreover, many of the differentiation protocols to obtain neuronal cultures are heterogeneous in cell types and many include glial cells ( Volpato and Webber, 2020 ). This may in itself influence the response of neurons to GCs knowing that glial cells such as astrocytes have also been shown to respond to GCs in vitro ( Heard et al, 2021 ; Choi et al, 2022 ). Additionally, a study by Cruceanu et al (2022) demonstrated cell-type specific responses to GCs in vitro , with differential-responses between different types of neural progenitors and neurons ( Notaras et al, 2021 ).…”

“…Investigating stress mechanisms in vitro (as most molecular biology assays) is a highly reductionist approach ( Regenmortel, 2004 ) to understanding stress, its underlying processes, and the mechanisms of SRMDs more broadly. That being said, in vitro stress models aim to investigate underlying mechanisms involved in the stress response, as a reaction to exposure to particular stress hormones, with the most studied hormone being GCs ( Bhargava et al, 2002 ; Kim et al, 2004 ; Cote-Vélez et al, 2005 ; Numakawa et al, 2009 ; Anacker et al, 2013 ; Bharti et al, 2018 ; Nürnberg et al, 2018 ; Yeo et al, 2019 ; Krontira et al, 2020 ; Cruceanu et al, 2021 ; Heard et al, 2021 ; Choi et al, 2022 ). In essence, one would assume that investigating effects of GCs in vitro seems straightforward.…”