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Proc Natl Acad Sci U S A. 2016 Mar 22;113(12):3185-90. doi: 10.1073/pnas.1521255113. Epub 2016 Mar 4.

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

Author information

1
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093;
2
Department of Pediatrics, Rady Children's Hospital-San Diego, San Diego, CA 92123; Stem Cell Program, Department of Cellular & Molecular Medicine, University of California, San Diego School of Medicine, Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037;
3
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0651;
4
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093;
5
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
6
Department of Pediatrics, Rady Children's Hospital-San Diego, San Diego, CA 92123; Stem Cell Program, Department of Cellular & Molecular Medicine, University of California, San Diego School of Medicine, Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037; aalmutairi@ucsd.edu muotri@ucsd.edu.
7
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093; aalmutairi@ucsd.edu muotri@ucsd.edu.

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.

KEYWORDS:

3D RTT modeling; 3D hydrogels; neuronal migration and maturation

PMID:
26944080
PMCID:
PMC4812712
DOI:
10.1073/pnas.1521255113
[Indexed for MEDLINE]
Free PMC Article

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