Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction

Zhen Ning Zhang; Beatriz C. Freitas; Hao Qian; Jacques Lux; Allan Acab; Cleber A. Trujillo; Roberto H. Herai; Viet Anh Nguyen Huu; Jessica H. Wen; Shivanjali Joshi-Barr; Jerome V. Karpiak; Adam J. Engler; Xiang Dong Fu; Alysson R. Muotri; Adah Almutairi

doi:10.1073/pnas.1521255113

Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction

Zhen Ning Zhang, Beatriz C. Freitas, Hao Qian, Jacques Lux, Allan Acab, Cleber A. Trujillo, Roberto H. Herai, Viet Anh Nguyen Huu, Jessica H. Wen, Shivanjali Joshi-Barr, Jerome V. Karpiak, Adam J. Engler, Xiang Dong Fu, Alysson R. Muotri, Adah Almutairi

Research output: Contribution to journal › Article › peer-review

125 Scopus citations

Abstract

Probing a wide range of cellular phenotypes in neurodevelopmental disorders using patient-derived neural progenitor cells (NPCs) can be facilitated by 3D assays, as 2D systems cannot entirely recapitulate the arrangement of cells in the brain. Here, we developed a previously unidentified 3D migration and differentiation assay in layered hydrogels to examine how these processes are affected in neurodevelopmental disorders, such as Rett syndrome. Our soft 3D system mimics the brain environment and accelerates maturation of neurons from human induced pluripotent stem cell (iPSC)-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. Using this platform, we revealed a genotype-specific effect of methyl-CpG-binding protein-2 (MeCP2) dysfunction on iPSC-derived neuronal migration and maturation (reduced neurite outgrowth and fewer synapses) in 3D layered hydrogels. Thus, this 3D system expands the range of neural phenotypes that can be studied in vitro to include those influenced by physical and mechanical stimuli or requiring specific arrangements of multiple cell types.

Original language	English (US)
Pages (from-to)	3185-3190
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	12
DOIs	https://doi.org/10.1073/pnas.1521255113
State	Published - Mar 22 2016

Keywords

3D RTT modeling
3D hydrogels
Neuronal migration and maturation

ASJC Scopus subject areas

General

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10.1073/pnas.1521255113

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Zhang, Z. N., Freitas, B. C., Qian, H., Lux, J., Acab, A., Trujillo, C. A., Herai, R. H., Huu, V. A. N., Wen, J. H., Joshi-Barr, S., Karpiak, J. V., Engler, A. J., Fu, X. D., Muotri, A. R., & Almutairi, A. (2016). Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction. Proceedings of the National Academy of Sciences of the United States of America, 113(12), 3185-3190. https://doi.org/10.1073/pnas.1521255113

Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction. / Zhang, Zhen Ning; Freitas, Beatriz C.; Qian, Hao et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 12, 22.03.2016, p. 3185-3190.

Research output: Contribution to journal › Article › peer-review

Zhang, ZN, Freitas, BC, Qian, H, Lux, J, Acab, A, Trujillo, CA, Herai, RH, Huu, VAN, Wen, JH, Joshi-Barr, S, Karpiak, JV, Engler, AJ, Fu, XD, Muotri, AR & Almutairi, A 2016, 'Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 12, pp. 3185-3190. https://doi.org/10.1073/pnas.1521255113

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title = "Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction",

abstract = "Probing a wide range of cellular phenotypes in neurodevelopmental disorders using patient-derived neural progenitor cells (NPCs) can be facilitated by 3D assays, as 2D systems cannot entirely recapitulate the arrangement of cells in the brain. Here, we developed a previously unidentified 3D migration and differentiation assay in layered hydrogels to examine how these processes are affected in neurodevelopmental disorders, such as Rett syndrome. Our soft 3D system mimics the brain environment and accelerates maturation of neurons from human induced pluripotent stem cell (iPSC)-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. Using this platform, we revealed a genotype-specific effect of methyl-CpG-binding protein-2 (MeCP2) dysfunction on iPSC-derived neuronal migration and maturation (reduced neurite outgrowth and fewer synapses) in 3D layered hydrogels. Thus, this 3D system expands the range of neural phenotypes that can be studied in vitro to include those influenced by physical and mechanical stimuli or requiring specific arrangements of multiple cell types.",

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note = "Funding Information: ACKNOWLEDGMENTS. The authors gratefully acknowledge the NIH New Innovator Awards (DP2OD006499 and DP2OD006495), NIH (5R01EY024134-02), the California Institute for Regenerative Medicine (TR2-01814 and TR4-06747), the International Rett Syndrome Foundation (IRSF Grant 2915 and Grant 2925), a National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Grant (to A.R.M.), and King Abdulaziz City for Science and Technology (through the KACST-University of California, San Diego Center for Excellence in Nanomedicine and Engineering) for funding.",

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AU - Freitas, Beatriz C.

AU - Qian, Hao

AU - Lux, Jacques

AU - Acab, Allan

AU - Trujillo, Cleber A.

AU - Herai, Roberto H.

AU - Huu, Viet Anh Nguyen

AU - Wen, Jessica H.

AU - Joshi-Barr, Shivanjali

AU - Karpiak, Jerome V.

AU - Engler, Adam J.

AU - Fu, Xiang Dong

AU - Muotri, Alysson R.

AU - Almutairi, Adah

N1 - Funding Information: ACKNOWLEDGMENTS. The authors gratefully acknowledge the NIH New Innovator Awards (DP2OD006499 and DP2OD006495), NIH (5R01EY024134-02), the California Institute for Regenerative Medicine (TR2-01814 and TR4-06747), the International Rett Syndrome Foundation (IRSF Grant 2915 and Grant 2925), a National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Grant (to A.R.M.), and King Abdulaziz City for Science and Technology (through the KACST-University of California, San Diego Center for Excellence in Nanomedicine and Engineering) for funding.

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N2 - Probing a wide range of cellular phenotypes in neurodevelopmental disorders using patient-derived neural progenitor cells (NPCs) can be facilitated by 3D assays, as 2D systems cannot entirely recapitulate the arrangement of cells in the brain. Here, we developed a previously unidentified 3D migration and differentiation assay in layered hydrogels to examine how these processes are affected in neurodevelopmental disorders, such as Rett syndrome. Our soft 3D system mimics the brain environment and accelerates maturation of neurons from human induced pluripotent stem cell (iPSC)-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. Using this platform, we revealed a genotype-specific effect of methyl-CpG-binding protein-2 (MeCP2) dysfunction on iPSC-derived neuronal migration and maturation (reduced neurite outgrowth and fewer synapses) in 3D layered hydrogels. Thus, this 3D system expands the range of neural phenotypes that can be studied in vitro to include those influenced by physical and mechanical stimuli or requiring specific arrangements of multiple cell types.

AB - Probing a wide range of cellular phenotypes in neurodevelopmental disorders using patient-derived neural progenitor cells (NPCs) can be facilitated by 3D assays, as 2D systems cannot entirely recapitulate the arrangement of cells in the brain. Here, we developed a previously unidentified 3D migration and differentiation assay in layered hydrogels to examine how these processes are affected in neurodevelopmental disorders, such as Rett syndrome. Our soft 3D system mimics the brain environment and accelerates maturation of neurons from human induced pluripotent stem cell (iPSC)-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. Using this platform, we revealed a genotype-specific effect of methyl-CpG-binding protein-2 (MeCP2) dysfunction on iPSC-derived neuronal migration and maturation (reduced neurite outgrowth and fewer synapses) in 3D layered hydrogels. Thus, this 3D system expands the range of neural phenotypes that can be studied in vitro to include those influenced by physical and mechanical stimuli or requiring specific arrangements of multiple cell types.

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Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction

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