title: Direct reprogramming of human astrocytes into neural stem cells and neurons.
abstract: Generating neural stem cells and neurons from reprogrammed human astrocytes is a potential strategy for neurological repair. Here we show dedifferentiation of human cortical astrocytes into the neural stem/progenitor phenotype to obtain progenitor and mature cells with a neural fate. Ectopic expression of the reprogramming factors OCT4, SOX2, or NANOG into astrocytes in specific cytokine/culture conditions activated the neural stem gene program and induced generation of cells expressing neural stem/precursor markers. Pure CD44+ mature astrocytes also exhibited this lineage commitment change and did not require passing through a pluripotent state. These astrocyte-derived neural stem cells gave rise to neurons, astrocytes, and oligodendrocytes and showed in vivo engraftment properties. ASCL1 expression further promoted neuronal phenotype acquisition in vitro and in vivo. Methylation analysis showed that epigenetic modifications underlie this process. The restoration of multipotency from human astrocytes has potential in cellular reprogramming of endogenous central nervous system cells in neurological disorders.
authors.affiliation: Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ca'Granda Maggiore Hospital Policlinico, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
authors.forename: Monica
authors.initials: M
authors.lastname: Nizzardo
authors.forename: Chiara
authors.initials: C
authors.lastname: Simone
authors.forename: Marianna
authors.initials: M
authors.lastname: Falcone
authors.forename: Chiara
authors.initials: C
authors.lastname: Donadoni
authors.forename: Sabrina
authors.initials: S
authors.lastname: Salani
authors.forename: Federica
authors.initials: F
authors.lastname: Rizzo
authors.forename: Martina
authors.initials: M
authors.lastname: Nardini
authors.forename: Giulietta
authors.initials: G
authors.lastname: Riboldi
authors.forename: Francesca
authors.initials: F
authors.lastname: Magri
authors.forename: Chiara
authors.initials: C
authors.lastname: Zanetta
authors.forename: Irene
authors.initials: I
authors.lastname: Faravelli
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism*; D054337:Cell Dedifferentiation / Q000235:genetics / Q000502:physiology; D054338:Cell Transdifferentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D019175:DNA Methylation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism; D000071317:Nanog Homeobox Protein; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000637:transplantation; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors