Neurons derived from human-induced pluripotent stem cells express mu and kappa opioid receptors

Ju, Zhihai; Liu, Xuan; Ren, Yaoyao; Shu, Luo-Wa; Yan, Yanhong; Cui, Xu

doi:10.4103/1673-5374.295341

Cited by 9 publications

(5 citation statements)

References 42 publications

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“…7e–h ). These results indicate that our current iteration of MORp constructs appear to show selectivity for human cell types known to express MOR (and/or the OPRM1 gene) when compared to cells shown to possess low expression of this receptor/gene, as demonstrated both from previous studies 68 , 69 and our own gene expression analyses of these two cultures, which found nociceptor cells to indeed express higher trending levels of OPRM1 than the cardiomyocyte cells in which our transduction experiments were performed (Supplementary Fig. 15b ).…”

Section: Resultssupporting

confidence: 75%

Human OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to μ-opioidergic cell types

Salimando,

Tremblay,

Kimmey

et al. 2023

Nat Commun

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With concurrent global epidemics of chronic pain and opioid use disorders, there is a critical need to identify, target and manipulate specific cell populations expressing the mu-opioid receptor (MOR). However, available tools and transgenic models for gaining long-term genetic access to MOR+ neural cell types and circuits involved in modulating pain, analgesia and addiction across species are limited. To address this, we developed a catalog of MOR promoter (MORp) based constructs packaged into adeno-associated viral vectors that drive transgene expression in MOR+ cells. MORp constructs designed from promoter regions upstream of the mouse Oprm1 gene (mMORp) were validated for transduction efficiency and selectivity in endogenous MOR+ neurons in the brain, spinal cord, and periphery of mice, with additional studies revealing robust expression in rats, shrews, and human induced pluripotent stem cell (iPSC)-derived nociceptors. The use of mMORp for in vivo fiber photometry, behavioral chemogenetics, and intersectional genetic strategies is also demonstrated. Lastly, a human designed MORp (hMORp) efficiently transduced macaque cortical OPRM1+ cells. Together, our MORp toolkit provides researchers cell type specific genetic access to target and functionally manipulate mu-opioidergic neurons across a range of vertebrate species and translational models for pain, addiction, and neuropsychiatric disorders.

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Section: Resultssupporting

confidence: 75%

Human OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to μ-opioidergic cell types

Salimando,

Tremblay,

Kimmey

et al. 2023

Nat Commun

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“…MORs and KORs are the first opioid-receptors to appear in the fetal brain, while DORs appear postnatally ( Rius et al, 1991 ; Zhu et al, 1998 ). This finding highlights the possibility that opioids may have distinct effects depending on developmental stage, making the MOR and KOR expressing neurons generated by Ju et al (2021) an exceedingly relevant model system for POE. In addition, because these neurons originate from exfoliated renal epithelial cells in urine, they afford a unique level of scalability based on the ready supply of source material that can be clinically and non-invasively obtained from maternal OUD subjects or opioid-exposed neonates ( Ju et al, 2021 ).…”

Section: Brain Organoid Models Of Prenatal Opioid Exposurementioning

confidence: 86%

“…The first neuronal cultures relevant to the study of POE were developed by Ju et al (2021) , who used iPSCs to generate neurons expressing μ-(MOR) and κ-opioid receptors (KOR). Opioids bind to three major opioid receptors throughout the central and peripheral nervous systems: mu-(MOR), kappa (KOR), and delta (DOR).…”

Section: Brain Organoid Models Of Prenatal Opioid Exposurementioning

confidence: 99%

“…One problem, however, was that the neurons generated by Ju et al (2021) did not possess any regional or subtype identity. Consequently, recent efforts have focused on generating cell types more specific to mechanisms of opioid action in vivo .…”

Section: Brain Organoid Models Of Prenatal Opioid Exposurementioning

confidence: 99%

“…2021) an exceedingly relevant model system for POE. In addition, because these neurons originate from exfoliated renal epithelial cells in urine, they afford a unique level of scalability based on the ready supply of source material that can be clinically and non-invasively obtained from maternal OUD subjects or opioidexposed neonates (Ju et al, 2021). One problem, however, was that the neurons generated by Ju et al (2021) did not possess any regional or subtype identity.…”

Section: Technical Contributions Of 2d Neuronal Models Of Prenatal Op...mentioning

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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Engineering Sensory Ganglion Multicellular System to Model Tissue Nerve Ingrowth

Ma,

Eglauf,

Grad

et al. 2023

Advanced Science

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Discogenic pain is associated with deep nerve ingrowth in annulus fibrosus tissue (AF) of intervertebral disc (IVD). To model AF nerve ingrowth, primary bovine dorsal root ganglion (DRG) micro‐scale tissue units are spatially organised around an AF explant by mild hydrodynamic forces within a collagen matrix. This results in a densely packed multicellular system mimicking the native DRG tissue morphology and a controlled AF‐neuron distance. Such a multicellular organisation is essential to evolve populational‐level cellular functions and in vivo‐like morphologies. Pro‐inflammatory cytokine‐primed AF demonstrates its neurotrophic and neurotropic effects on nociceptor axons. Both effects are dependent on the AF‐neuron distance underpinning the role of recapitulating inter‐tissue/organ anatomical proximity when investigating their crosstalk. This is the first in vitro model studying AF nerve ingrowth by engineering mature and large animal tissues in a morphologically and physiologically relevant environment. The new approach can be used to biofabricate multi‐tissue/organ models for untangling pathophysiological conditions and develop novel therapies.

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Neurons derived from human-induced pluripotent stem cells express mu and kappa opioid receptors

Cited by 9 publications

References 42 publications

Human OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to μ-opioidergic cell types

Human OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to μ-opioidergic cell types

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

Engineering Sensory Ganglion Multicellular System to Model Tissue Nerve Ingrowth

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