Cerebral Organoids to Study Central Mechanisms of Pain: The Effect of Stem Cell Secretome on Opioid Receptors and Neuroplasticity

Fernandes, Aline Marie; Campos, Jonas; Silva, Deolinda; Antunes, Sandra; Lima, Rui; Coelho, Claudio; Marote, Ana; Almeida, Hugo; Silva, Nuno; Salgado, António J.

doi:10.1089/scd.2022.0116

Cited by 7 publications

(11 citation statements)

References 91 publications

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“…In contrast, chronic fentanyl treatment arrested the fate determination of neural progenitor cells and altered the expression of synaptic activity and neuronal projection pathways ( Kim et al, 2021 ). These findings were analogous to the neurodevelopmental effects of methadone and buprenorphine reported in cortical or cerebral organoids ( Wu et al, 2020 ; Yao et al, 2020 , 2023 ; Fernandes et al, 2022 ; Nieto-Estévez et al, 2022 ; Dwivedi et al, 2023 ). All the same, this study by Kim et al (2021) unfurled a list of novel possibilities when it came to studies of POE in organoids, especially regarding the opioid-types and brain-regions modeled.…”

Section: Brain Organoid Models Of Prenatal Opioid Exposuresupporting

confidence: 81%

“…With respect to the latter issue, only three articles included in this review mention using 3D cultures to recapitulate brain regions outside of the forebrain ( Kim et al, 2021 ; Fernandes et al, 2022 ; Strong et al, 2023 ) ( Tables 1 , 2 ). In future, the increased inclusion of midbrain, hindbrain, and brainstem organoid cultures may help provide greater insight into the mechanisms underlying OUD and POE ( Tieng et al, 2014 ; Jo et al, 2016 ; Qian et al, 2016 ; Eura et al, 2020 ; Nickels et al, 2020 ; Valiulahi et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Unlike Nieto-Estévez et al (2022) , the iPSC-derived cerebral organoids (CeO) generated by Fernandes et al (2022) were confirmed to express MOR, DOR, and KOR within 30 days of differentiation in both neurons and glial cells. The expression of opioid receptors on glial cells in this model was unique, given discrepancies in findings regarding the presence of these receptors on astrocytes in vivo ( Stiene-Martin et al, 2001 ; Machelska and Celik, 2020 ).…”

Section: Brain Organoid Models Of Prenatal Opioid Exposurementioning

confidence: 99%

“…The expression of opioid receptors on glial cells in this model was unique, given discrepancies in findings regarding the presence of these receptors on astrocytes in vivo ( Stiene-Martin et al, 2001 ; Machelska and Celik, 2020 ). Moreover, this was first use of a region non-specific organoid to study POE in vitro ( Fernandes et al, 2022 ). Using this model, Fernandes et al (2022) found that modulating opioid receptor activity using buprenorphine increased apoptosis, astrogliogenesis, glial cell maturation, and dopamine release in CeO cultures, consequences of chronic opioid exposure that have been observed in prior studies.…”

Section: Brain Organoid Models Of Prenatal Opioid Exposurementioning

confidence: 99%

“…Moreover, this was first use of a region non-specific organoid to study POE in vitro ( Fernandes et al, 2022 ). Using this model, Fernandes et al (2022) found that modulating opioid receptor activity using buprenorphine increased apoptosis, astrogliogenesis, glial cell maturation, and dopamine release in CeO cultures, consequences of chronic opioid exposure that have been observed in prior studies. In parallel, the team also subjected their CeOs to the bone marrow stem cell secretome (BMSCSec), which has been explored as an antinociceptive treatment alternative to opioid-based analgesia ( Brini et al, 2017 ; Gama et al, 2018 ; Khatab et al, 2018 ).…”

Section: Brain Organoid Models Of Prenatal Opioid Exposurementioning

confidence: 99%

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Investigating the neurobiology of maternal opioid use disorder and prenatal opioid exposure using brain organoid technology

Dwivedi,

Haddad

2024

Front. Cell. Neurosci.

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Over the past two decades, Opioid Use Disorder (OUD) among pregnant women has become a major global public health concern. OUD has been characterized as a problematic pattern of opioid use despite adverse physical, psychological, behavioral, and or social consequences. Due to the relapsing–remitting nature of this disorder, pregnant mothers are chronically exposed to exogenous opioids, resulting in adverse neurological and neuropsychiatric outcomes. Collateral fetal exposure to opioids also precipitates severe neurodevelopmental and neurocognitive sequelae. At present, much of what is known regarding the neurobiological consequences of OUD and prenatal opioid exposure (POE) has been derived from preclinical studies in animal models and postnatal or postmortem investigations in humans. However, species-specific differences in brain development, variations in subject age/health/background, and disparities in sample collection or storage have complicated the interpretation of findings produced by these explorations. The ethical or logistical inaccessibility of human fetal brain tissue has also limited direct examinations of prenatal drug effects. To circumvent these confounding factors, recent groups have begun employing induced pluripotent stem cell (iPSC)-derived brain organoid technology, which provides access to key aspects of cellular and molecular brain development, structure, and function in vitro. In this review, we endeavor to encapsulate the advancements in brain organoid culture that have enabled scientists to model and dissect the neural underpinnings and effects of OUD and POE. We hope not only to emphasize the utility of brain organoids for investigating these conditions, but also to highlight opportunities for further technical and conceptual progress. Although the application of brain organoids to this critical field of research is still in its nascent stages, understanding the neurobiology of OUD and POE via this modality will provide critical insights for improving maternal and fetal outcomes.

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