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.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Zhen-Ning
authors.initials: ZN
authors.lastname: Zhang
authors.affiliation: 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;
authors.forename: Beatriz C
authors.initials: BC
authors.lastname: Freitas
authors.affiliation: 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;
authors.forename: Hao
authors.initials: H
authors.lastname: Qian
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Jacques
authors.initials: J
authors.lastname: Lux
authors.affiliation: 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;
authors.forename: Allan
authors.initials: A
authors.lastname: Acab
authors.affiliation: 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;
authors.forename: Cleber A
authors.initials: CA
authors.lastname: Trujillo
authors.affiliation: 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;
authors.forename: Roberto H
authors.initials: RH
authors.lastname: Herai
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Viet Anh
authors.initials: VA
authors.lastname: Nguyen Huu
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Wen
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Shivanjali
authors.initials: S
authors.lastname: Joshi-Barr
authors.affiliation: 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;
authors.forename: Jerome V
authors.initials: JV
authors.lastname: Karpiak
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Engler
authors.affiliation: 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;
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093; aalmutairi@ucsd.edu muotri@ucsd.edu.
authors.forename: Adah
authors.initials: A
authors.lastname: Almutairi
mesh_terms: D002465:Cell Movement; D006801:Humans; D020100:Hydrogels; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D051783:Methyl-CpG-Binding Protein 2 / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*
chemical_list: D020100:Hydrogels; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2
keywords: 3D RTT modeling; 3D hydrogels; neuronal migration and maturation