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Efficient generation of lower induced motor neurons by coupling Ngn2 expression with developmental cues.
Limone, Francesco; Guerra San Juan, Irune; Mitchell, Jana M; Smith, Janell L M; Raghunathan, Kavya; Meyer, Daniel; Ghosh, Sulagna Dia; Couto, Alexander; Klim, Joseph R; Joseph, Brian J; Gold, John; Mello, Curtis J; Nemesh, James; Smith, Brittany M; Verhage, Matthijs; McCarroll, Steven A; Pietiläinen, Olli; Nehme, Ralda; Eggan, Kevin.
Afiliação
  • Limone F; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Centre for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Leiden University Medical Center, LUMC, 2333 ZA Leiden, the Netherlands. Electronic address: francesc
  • Guerra San Juan I; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Centre for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universitei
  • Mitchell JM; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Centre for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Smith JLM; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • Raghunathan K; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Centre for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Meyer D; Stanley Centre for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Ghosh SD; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Centre for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Couto A; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • Klim JR; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Centre for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Joseph BJ; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Departments of Pathology and Cell Biology, Columbia University Irving Medical Centre, New York, NY 10032, USA.
  • Gold J; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • Mello CJ; Stanley Centre for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Nemesh J; Stanley Centre for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Smith BM; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • Verhage M; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit, Amsterdam, the Netherlands; Human Genetics, Amsterdam University Medical Center, Amsterdam, the Netherlands.
  • McCarroll SA; Stanley Centre for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Pietiläinen O; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Centre for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
  • Nehme R; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Centre for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Eggan K; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: kevin.eggan@bmrn.com.
Cell Rep ; 42(1): 111896, 2023 01 31.
Article em En | MEDLINE | ID: mdl-36596304
ABSTRACT
Human pluripotent stem cells (hPSCs) are a powerful tool for disease modeling of hard-to-access tissues (such as the brain). Current protocols either direct neuronal differentiation with small molecules or use transcription-factor-mediated programming. In this study, we couple overexpression of transcription factor Neurogenin2 (Ngn2) with small molecule patterning to differentiate hPSCs into lower induced motor neurons (liMoNes/liMNs). This approach induces canonical MN markers including MN-specific Hb9/MNX1 in more than 95% of cells. liMNs resemble bona fide hPSC-derived MN, exhibit spontaneous electrical activity, express synaptic markers, and can contact muscle cells in vitro. Pooled, multiplexed single-cell RNA sequencing on 50 hPSC lines reveals reproducible populations of distinct subtypes of cervical and brachial MNs that resemble their in vivo, embryonic counterparts. Combining small molecule patterning with Ngn2 overexpression facilitates high-yield, reproducible production of disease-relevant MN subtypes, which is fundamental in propelling our knowledge of MN biology and its disruption in disease.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sinais (Psicologia) / Células-Tronco Pluripotentes Induzidas Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sinais (Psicologia) / Células-Tronco Pluripotentes Induzidas Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article