Single-Cell Assessment of Human Stem Cell-Derived Mesolimbic Models and Their Responses to Substances of Abuse
Abstract
:1. Introduction
2. Materials and Methods
2.1. hESC Cell Lines
2.2. Organoid Cultures
2.9. Statistical Analysis
3. Results
3.1. Development of Striatal and Midbrain Organoids Compatible with Early Assembloid Generation
3.2. scRNAseq Reveals Heterogeneous Compositions and Distinct Enrichments of GABAergic Subtypes in Seven 3D and 2D Striatal Models
3.3. Cell-Type-Specific Differential Gene-Expression Responses to Dopamine, Cocaine, and Morphine
3.4. Gene Set Enrichment Analysis of Cell-Type-Specific Responses to Dopamine, Cocaine, and Morphine
3.5. Bulk Analysis Reveals Roles for eIF2 and TGF-β Signaling
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Thompson, L.W. The Dopamine Hypothesis of Schizophrenia. Perspect. Psychiatr. Care 1990, 26, 18–23. [Google Scholar] [CrossRef]
- Gerfen, C.R.; Bolam, J.P. The Neuroanatomical Organization of the Basal Ganglia. Handb. Behav. Neurosci. 2010, 20, 3–28. [Google Scholar] [CrossRef]
- Surmeier, D.J.; Carrillo-Reid, L.; Bargas, J. Dopaminergic modulation of striatal neurons, circuits, and assemblies. Neuroscience 2011, 198, 3–18. [Google Scholar] [CrossRef]
- Hyman, S.E.; Malenka, R.C.; Nestler, E.J. Neural Mechanisms of Addiction: The Role of Reward-Related Learning and Memory. Annu. Rev. Neurosci. 2006, 29, 565–598. [Google Scholar] [CrossRef]
- Nestler, E.J. Molecular basis of long-term plasticity underlying addiction. Nat. Rev. Neurosci. 2001, 2, 119–128. [Google Scholar] [CrossRef]
- Nestler, E.J. Historical review: Molecular and cellular mechanisms of opiate and cocaine addiction. Trends Pharmacol. Sci. 2004, 25, 210–218. [Google Scholar] [CrossRef] [PubMed]
- Renthal, W.; Kumar, A.; ** rat brain—Implications for perinatal buprenorphine exposure. Reprod. Toxicol. 2018, 78, 81–89. [Google Scholar] [CrossRef] [PubMed]
- Stiene-Martin, A.; Knapp, P.E.; Martin, K.; Gurwell, J.A.; Ryan, S.; Thornton, S.R.; Smith, F.L.; Hauser, K.F. Opioid system diversity in develo** neurons, astroglia, and oligodendroglia in the subventricular zone and striatum: Impact on gliogenesis in vivo. Glia 2001, 36, 78–88. [Google Scholar] [CrossRef]
- Boggess, T.; Williamson, J.C.; Niebergall, E.B.; Sexton, H.; Mazur, A.; Egleton, R.D.; Grover, L.M.; Risher, W.C. Alterations in Excitatory and Inhibitory Synaptic Development within the Mesolimbic Dopamine Pathway in a Mouse Model of Prenatal Drug Exposure. Front. Pediatr. 2021, 9, 794544. [Google Scholar] [CrossRef]
- Konijnenberg, C.; Melinder, A. Prenatal exposure to methadone and buprenorphine: A review of the potential effects on cognitive development. Child. Neuropsychol. 2011, 17, 495–519. [Google Scholar] [CrossRef]
- Mohan, V.; Edamakanti, C.R.; Pathak, A. Editorial: Role of extracellular matrix in neurodevelopment and neurodegeneration. Front. Cell Neurosci. 2023, 17, 1135555. [Google Scholar] [CrossRef] [PubMed]
- Lee, C.T.; Chen, J.; Hayashi, T.; Tsai, S.Y.; Sanchez, J.F.; Errico, S.L.; Amable, R.; Su, T.P.; Lowe, R.H.; Huestis, M.A.; et al. A mechanism for the inhibition of neural progenitor cell proliferation by cocaine. PLoS Med. 2008, 5, e117. [Google Scholar] [CrossRef] [PubMed]
- Martins, S.G.; Zilhão, R.; Thorsteinsdóttir, S.; Carlos, A.R. Linking Oxidative Stress and DNA Damage to Changes in the Expression of Extracellular Matrix Components. Front. Genet. 2021, 12, 673002. [Google Scholar] [CrossRef] [PubMed]
- Kyriakis, J.M.; Avruch, J. MAP Kinase Pathways. In Compendium of Inflammatory Diseases; Parnham, M.J., Ed.; Springer: Basel, Switzerland, 2016; pp. 892–908. [Google Scholar] [CrossRef]
- Poon, H.F.; Abdullah, L.; Mullan, M.A.; Mullan, M.J.; Crawford, F.C. Cocaine-induced oxidative stress precedes cell death in human neuronal progenitor cells. Neurochem. Int. 2007, 50, 69–73. [Google Scholar] [CrossRef] [PubMed]
- Nasiraei-Moghadam, S.; Sherafat, M.A.; Safari, M.S.; Moradi, F.; Ahmadiani, A.; Dargahi, L. Reversal of prenatal morphine exposure-induced memory deficit in male but not female rats. J. Mol. Neurosci. 2013, 50, 58–69. [Google Scholar] [CrossRef]
- Yao, H.; Wu, W.; Cerf, I.; Zhao, H.W.; Wang, J.; Negraes, P.D.; Muotri, A.R.; Haddad, G.G. Methadone interrupts neural growth and function in human cortical organoids. Stem Cell Res. 2020, 49, 102065. [Google Scholar] [CrossRef]
- Zhu, H.; Zhuang, D.; Lou, Z.; Lai, M.; Fu, D.; Hong, Q.; Liu, H.; Zhou, W. Akt and its phosphorylation in nucleus accumbens mediate heroin-seeking behavior induced by cues in rats. Addict. Biol. 2021, 26, e13013. [Google Scholar] [CrossRef]
- Lu, L.; Koya, E.; Zhai, H.; Hope, B.T.; Shaham, Y. Role of ERK in cocaine addiction. Trends Neurosci. 2006, 29, 695–703. [Google Scholar] [CrossRef] [PubMed]
- Gancarz-Kausch, A.M.; Schroeder, G.L.; Panganiban, C.; Adank, D.; Humby, M.S.; Kausch, M.A.; Clark, S.D.; Dietz, D.M. Transforming growth factor beta receptor 1 is increased following abstinence from cocaine self-administration, but not cocaine sensitization. PLoS ONE 2013, 8, e83834. [Google Scholar] [CrossRef]
- Edlund, S.; Landström, M.; Heldin, C.H.; Aspenström, P. Transforming growth factor-β-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol. Biol. Cell 2002, 13, 902–914. [Google Scholar] [CrossRef]
- Wrana, J.L. Signaling by the TGFβ superfamily. Cold Spring Harb. Perspect. Biol. 2013, 5, a011197. [Google Scholar] [CrossRef]
- Meyers, E.A.; Kessler, J.A. TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function. Cold Spring Harb. Perspect. Biol. 2017, 9, a022244. [Google Scholar] [CrossRef] [PubMed]
- Aldrich, A.; Kielian, T. Central nervous system fibrosis is associated with fibrocyte-like infiltrates. Am. J. Pathol. 2011, 179, 2952–2962. [Google Scholar] [CrossRef]
- Meiser, J.; Weindl, D.; Hiller, K. Complexity of dopamine metabolism. Cell Commun. Signal 2013, 11, 34. [Google Scholar] [CrossRef] [PubMed]
- Cai, Y.; Yang, L.; Hu, G.; Chen, X.; Niu, F.; Yuan, L.; Liu, H.; **ong, H.; Arikkath, J.; Buch, S. Regulation of morphine-induced synaptic alterations: Role of oxidative stress, ER stress, and autophagy. J. Cell Biol. 2016, 215, 245–258. [Google Scholar] [CrossRef] [PubMed]
- Biswas, K.; Alexander, K.; Francis, M.M. Reactive Oxygen Species: Angels and Demons in the Life of a Neuron. NeuroSci 2022, 3, 130–145. [Google Scholar] [CrossRef]
- Cnop, M.; Toivonen, S.; Igoillo-Esteve, M.; Salpea, P. Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells. Mol. Metab. 2017, 6, 1024–1039. [Google Scholar] [CrossRef] [PubMed]
- Ercan, E.; Han, J.M.; Di Nardo, A.; Winden, K.; Han, M.J.; Hoyo, L.; Saffari, A.; Leask, A.; Geschwind, D.H.; Sahin, M. Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex. J. Exp. Med. 2017, 214, 681–697. [Google Scholar] [CrossRef] [PubMed]
- Singh, D.; Srivastava, S.K.; Chaudhuri, T.K.; Upadhyay, G. Multifaceted role of matrix metalloproteinases (MMPs). Front. Mol. Biosci. 2015, 2, 19. [Google Scholar] [CrossRef] [PubMed]
- Adil, M.M.; Gaj, T.; Rao, A.T.; Kulkarni, R.U.; Fuentes, C.M.; Ramadoss, G.N.; Ekman, F.K.; Miller, E.W.; Schaffer, D.V. hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model. Stem Cell Rep. 2018, 10, 1481–1491. [Google Scholar] [CrossRef]
- Kindberg, A.A.; Bendriem, R.M.; Spivak, C.E.; Chen, J.; Handreck, A.; Lupica, C.R.; Liu, J.; Freed, W.J.; Lee, C.T. An in vitro model of human neocortical development using pluripotent stem cells: Cocaine-induced cytoarchitectural alterations. DMM Dis. Model. Mech. 2014, 7, 1397–1405. [Google Scholar] [CrossRef]
- White, F.J.; Kalivas, P.W. Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol. Depend. 1998, 51, 141–153. [Google Scholar] [CrossRef]
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Rudibaugh, T.P.; Tam, R.W.; Estridge, R.C.; Stuppy, S.R.; Keung, A.J. Single-Cell Assessment of Human Stem Cell-Derived Mesolimbic Models and Their Responses to Substances of Abuse. Organoids 2024, 3, 126-147. https://doi.org/10.3390/organoids3020009
Rudibaugh TP, Tam RW, Estridge RC, Stuppy SR, Keung AJ. Single-Cell Assessment of Human Stem Cell-Derived Mesolimbic Models and Their Responses to Substances of Abuse. Organoids. 2024; 3(2):126-147. https://doi.org/10.3390/organoids3020009
Chicago/Turabian StyleRudibaugh, Thomas P., Ryan W. Tam, R. Chris Estridge, Samantha R. Stuppy, and Albert J. Keung. 2024. "Single-Cell Assessment of Human Stem Cell-Derived Mesolimbic Models and Their Responses to Substances of Abuse" Organoids 3, no. 2: 126-147. https://doi.org/10.3390/organoids3020009