Inhibition of glycogen synthase kinase-3 enhances the differentiation and reduces the proliferation of adult human olfactory epithelium neural precursors

Manceur, Aziza; Tseng, Michael T.; Holowacz, Tamara; Witterick, Ian; Weksberg, Rosanna; McCurdy, Richard D.; Warsh, Jerry J.; Audet, Julie

doi:10.1016/j.yexcr.2011.06.004

Cited by 16 publications

(9 citation statements)

References 60 publications

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“…RO4929097, a member of the secretase inhibitor family, was included to enhance neurogenesis by interfering with Notch signaling , . CHIR99021, acting as a Wnt agonist by selectively inhibiting glycogen synthase kinase 3β , was used in our protocol to accelerate neural crest formation and specification of sensory neurons , . SU5402, a potent inhibitor of FGFR1 signaling, was also applied not only to facilitate specification of neuroectodermal fate via PAX6 induction among human iPSCs but also to promote sensory neuron differentiation after neuroectoderm formation .…”

Section: Discussionmentioning

confidence: 99%

Human Induced Pluripotent Cell-Derived Sensory Neurons for Fate Commitment of Bone Marrow-Derived Schwann Cells: Implications for Remyelination Therapy

Cai

Han

et al. 2016

Stem Cells Translational Medicine

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Strategies that exploit induced pluripotent stem cells (iPSCs) to derive neurons have relied on cocktails of cytokines and growth factors to bias cell‐signaling events in the course of fate choice. These are often costly and inefficient, involving multiple steps. In this study, we took an alternative approach and selected 5 small‐molecule inhibitors of key signaling pathways in an 8‐day program to induce differentiation of human iPSCs into sensory neurons, reaching ≥80% yield in terms of marker proteins. Continuing culture in maintenance medium resulted in neuronal networks immunopositive for synaptic vesicle markers and vesicular glutamate transporters suggestive of excitatory neurotransmission. Subpopulations of the derived neurons were electrically excitable, showing tetrodotoxin‐sensitive action potentials in patch‐clamp experiments. Coculture of the derived neurons with rat Schwann cells under myelinating conditions resulted in upregulated levels of neuronal neuregulin 1 type III in conjunction with the phosphorylated receptors ErbB2 and ErbB3, consistent with amenability of the neuritic network to myelination. As surrogates of embryonic dorsal root ganglia neurons, the derived sensory neurons provided contact‐dependent cues to commit bone marrow‐derived Schwann cell‐like cells to the Schwann cell fate. Our rapid and efficient induction protocol promises not only controlled differentiation of human iPSCs into sensory neurons, but also utility in the translation to a protocol whereby human bone marrow‐derived Schwann cells become available for autologous transplantation and remyelination therapy. Stem Cells Translational Medicine 2017;6:369–381

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Section: Discussionmentioning

confidence: 99%

Human Induced Pluripotent Cell-Derived Sensory Neurons for Fate Commitment of Bone Marrow-Derived Schwann Cells: Implications for Remyelination Therapy

Cai

Han

et al. 2016

Stem Cells Translational Medicine

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“…Glycogen synthase kinase-3 (GSK3) is an enzyme that functions in many signaling pathways, including those involved in development. Inhibitors of GSK3, such as CHIR99021 used in our protocol, enhance neurogenesis [50], [51]. We also included RO4929097, a member of the γ-secretase inhibitor family that accelerates neural induction by interfering with Notch signaling [46], [52].…”

Section: Discussionmentioning

confidence: 99%

Human Sensory Neurons Derived from Induced Pluripotent Stem Cells Support Varicella-Zoster Virus Infection

et al. 2012

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After primary infection, varicella-zoster virus (VZV) establishes latency in neurons of the dorsal root and trigeminal ganglia. Many questions concerning the mechanism of VZV pathogenesis remain unanswered, due in part to the strict host tropism and inconsistent availability of human tissue obtained from autopsies and abortions. The recent development of induced pluripotent stem (iPS) cells provides great potential for the study of many diseases. We previously generated human iPS cells from skin fibroblasts by introducing four reprogramming genes with non-integrating adenovirus. In this study, we developed a novel protocol to generate sensory neurons from iPS cells. Human iPS cells were exposed to small molecule inhibitors for 10 days, which efficiently converted pluripotent cells into neural progenitor cells (NPCs). The NPCs were then exposed for two weeks to growth factors required for their conversion to sensory neurons. The iPS cell-derived sensory neurons were characterized by immunocytochemistry, flow cytometry, RT-qPCR, and electrophysiology. After differentiation, approximately 80% of the total cell population expressed the neuron-specific protein, βIII-tubulin. Importantly, 15% of the total cell population co-expressed the markers Brn3a and peripherin, indicating that these cells are sensory neurons. These sensory neurons could be infected by both VZV and herpes simplex virus (HSV), a related alphaherpesvirus. Since limited neuronal populations are capable of supporting the entire VZV and HSV life cycles, our iPS-derived sensory neuron model may prove useful for studying alphaherpesvirus latency and reactivation.

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“…6BIO has been found to promote and inhibit the ex vivo expansion of umbillical cord blood hematopoietic stem cells (UCB HSCs) in low and high concentrations, respectively [116,117]. GSK-3 inhibition by 6BIO also causes a decrease in proliferation of adult olfactory epithelial human neural precursors accompanied by an increase of differentiation markers, thus suggesting the promotion of early neuronal differentiation [118]. Similarly, human mesenchymal stem cells (hMSCs) from bone marrow are regarded as putative osteoblast progenitors differentiating into osteoblasts in vitro.…”

Section: Effect On Stem Cells and Progenitorsmentioning

confidence: 99%

From Tyrian Purple to Kinase Modulators: Naturally Halogenated Indirubins and Synthetic Analogues

Vougogiannopoulou

Skaltsounis

2012

Planta Med

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Inhibition of glycogen synthase kinase-3 enhances the differentiation and reduces the proliferation of adult human olfactory epithelium neural precursors

Cited by 16 publications

References 60 publications

Human Induced Pluripotent Cell-Derived Sensory Neurons for Fate Commitment of Bone Marrow-Derived Schwann Cells: Implications for Remyelination Therapy

Human Induced Pluripotent Cell-Derived Sensory Neurons for Fate Commitment of Bone Marrow-Derived Schwann Cells: Implications for Remyelination Therapy

Human Sensory Neurons Derived from Induced Pluripotent Stem Cells Support Varicella-Zoster Virus Infection

From Tyrian Purple to Kinase Modulators: Naturally Halogenated Indirubins and Synthetic Analogues

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