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Nature Oct 2022Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease. However, organoids lack the connectivity...
Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered.
Topics: Animals; Animals, Newborn; Autistic Disorder; Humans; Long QT Syndrome; Motivation; Neural Pathways; Neurons; Optogenetics; Organoids; Rats; Reward; Somatosensory Cortex; Stem Cells; Syndactyly
PubMed: 36224417
DOI: 10.1038/s41586-022-05277-w -
Seminars in Plastic Surgery Nov 2016Syndactyly is one of the most common congenital hand anomalies treated by pediatric plastic surgeons. Established principles of syndactyly separation dictate the timing... (Review)
Review
Syndactyly is one of the most common congenital hand anomalies treated by pediatric plastic surgeons. Established principles of syndactyly separation dictate the timing and order of syndactyly release, with the goals of surgery being the creation of an anatomically normal webspace, tension-free closure of soft tissue, and return of function to the fingers. Numerous surgical methods have been described, many of which involve the use of local flaps to reconstruct the commissure and full-thickness skin grafts for coverage of raw areas. Recently, reconstructive techniques without the use of skin grafts have been devised, which work well for certain indications. Special considerations are described for complete, complex, and syndromic syndactylies. Outcomes for simple syndactyly release are typically good when surgical principles are followed, whereas complex syndactyly release tends to have less-favorable outcomes and more complications.
PubMed: 27895538
DOI: 10.1055/s-0036-1593478 -
Nature May 2017The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from...
The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the Ca1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.
Topics: Autistic Disorder; Cell Line; Cell Movement; Cells, Cultured; Female; GABAergic Neurons; Glutamic Acid; Humans; Interneurons; Long QT Syndrome; Male; Models, Biological; Neurogenesis; Neurons; Pluripotent Stem Cells; Prosencephalon; Spheroids, Cellular; Synapses; Syndactyly
PubMed: 28445465
DOI: 10.1038/nature22330 -
The New England Journal of Medicine Jan 2018
Topics: Aged, 80 and over; Fingers; Humans; Male; Muscular Diseases; Pectoralis Muscles; Poland Syndrome
PubMed: 29298145
DOI: 10.1056/nejmicm1709713 -
Journal of Surgical Case Reports Dec 2020Here we present an interesting case of simple syndactyly and provide a narrative review of its incidence, associations and management.
Here we present an interesting case of simple syndactyly and provide a narrative review of its incidence, associations and management.
PubMed: 33391647
DOI: 10.1093/jscr/rjaa517