SHP2 mutations induce precocious gliogenesis of Noonan syndrome-derived iPSCs during neural development in vitro (vol 11, 209, 2020)

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BackgroundNoonan syndrome (NS) is a developmental disorder caused by mutations of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2). Although NS patients have diverse neurological manifestations, the mechanisms underlying the involvement of SHP2 mutations in neurological dysfunction remain elusive.MethodsInduced pluripotent stem cells generated from dermal fibroblasts of three NS-patients (NS-iPSCs) differentiated to the neural cells by using two different culture systems, 2D- and 3D-cultured systems in vitro.ResultsHere we represent that SHP2 mutations cause aberrant neural development. The NS-iPSCs exhibited impaired development of EBs in which BMP and TGF-beta signalings were activated. Defective early neuroectodermal development of NS-iPSCs recovered by inhibition of both signalings and further differentiated into NPCs. Intriguingly, neural cells developed from NS-NPCs exhibited abundancy of the glial cells, neurites of neuronal cells, and low electrophysiological property. Those aberrant phenotypes were also detected in NS-cerebral organoids. SHP2 inhibition in the NS-NPCs and NS-cerebral organoids ameliorated those anomalies such as biased glial differentiation and low neural activity.ConclusionOur findings demonstrate that SHP2 mutations contribute to precocious gliogenesis in NS-iPSCs during neural development in vitro.
Publisher
BMC
Issue Date
2020-07
Language
English
Article Type
Article
Citation

STEM CELL RESEARCH THERAPY, v.11, no.1

ISSN
1757-6512
DOI
10.1186/s13287-020-01709-4
URI
http://hdl.handle.net/10203/275496
Appears in Collection
MSE-Journal Papers(저널논문)BiS-Journal Papers(저널논문)BS-Journal Papers(저널논문)
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