Human induced pluripotent stem cells (iPSC) hold promise for modeling diseases in individual human genetic backgrounds and thus for developing precision medicine. Here, we generate sensorimotor organoids containing physiologically functional neuromuscular junctions (NMJs) and apply the model to different subgroups of amyotrophic lateral sclerosis (ALS). Using a range of molecular, genomic, and physiological techniques, we identify and characterize motor neurons and skeletal muscle, along with sensory neurons, astrocytes, microglia, and vasculature. Organoid cultures derived from multiple human iPSC lines generated from individuals with ALS and isogenic lines edited to harbor familial ALS mutations show impairment at the level of the NMJ, as detected by both contraction and immunocytochemical measurements. The physiological resolution of the human NMJ synapse, combined with the generation of major cellular cohorts exerting autonomous and non-cell autonomous effects in motor and sensory diseases, may prove valuable to understand the pathophysiological mechanisms of ALS.
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| http://dx.doi.org/10.1038/s41467-021-24776-4 | DOI Listing |
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- Researchers studied neural circuits in the brain important for sensorimotor processing and their links to neuropsychiatric disorders using advanced methods involving human pluripotent stem cells.
- They created specialized four-part "loop assembloids" that mimic key brain regions, allowing for the observation of synchronized neuronal activity and connectivity.
- This platform is valuable for investigating genetic influences on disorders like autism and Tourette syndrome, revealing unique patterns of neuronal behavior associated with these conditions.
Functional reconstruction of the impaired cortex and motor function by hMGEOs transplantation in stroke.
Biochem Biophys Res Commun
September 2023
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China; Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, China. Electronic address:
Stroke is the leading cause of death and long-term disability worldwide. But treatments are not available to promote functional recovery, and efficient therapies need to be investigated. Stem cell-based therapies hold great promise as potential technologies to restore function in brain disorders.
View Article and Find Full Text PDFCerebral organoids transplantation repairs infarcted cortex and restores impaired function after stroke.
NPJ Regen Med
May 2023
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
Stroke usually causes prolonged or lifelong disability, owing to the permanent loss of infarcted tissue. Although a variety of stem cell transplantation has been explored to improve neuronal defect behavior by enhancing neuroplasticity, it remains unknown whether the infarcted tissue can be reconstructed. We here cultured human cerebral organoids derived from human pluripotent stem cells (hPSCs) and transplanted them into the junction of the infarct core and the peri-infarct zone of NOD-SCID mice subjected to stroke.
View Article and Find Full Text PDFHuman sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions.
Nat Commun
August 2021
Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Human induced pluripotent stem cells (iPSC) hold promise for modeling diseases in individual human genetic backgrounds and thus for developing precision medicine. Here, we generate sensorimotor organoids containing physiologically functional neuromuscular junctions (NMJs) and apply the model to different subgroups of amyotrophic lateral sclerosis (ALS). Using a range of molecular, genomic, and physiological techniques, we identify and characterize motor neurons and skeletal muscle, along with sensory neurons, astrocytes, microglia, and vasculature.
View Article and Find Full Text PDFThe development of an in vitro cerebral organoid model for investigating the pathomolecular mechanisms associated with the central nervous system involvement in Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE).
Nucleosides Nucleotides Nucleic Acids
November 2019
a Molecular & Clinical Sciences Research Institute, St. George's, University of London, United Kingdom.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare disorder caused by mutations in the thymidine phosphorylase gene (TYMP), leading to secondary aberrations to the mitochondrial genome. The disease is characterised by gastrointestinal dysmotility, sensorimotor peripheral neuropathy and leukoencephalopathy. The understanding of the molecular mechanisms that underlie the central nervous system (CNS) is hindered by the lack of a representative disease model; to address this we have developed an in vitro 3-D cerebral organoid of MNGIE.
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