title: Direct lineage reprogramming of mouse fibroblasts to functional midbrain dopaminergic neuronal progenitors.
abstract: The direct lineage reprogramming of somatic cells to other lineages by defined factors has led to innovative cell-fate-change approaches for providing patient-specific cells. Recent reports have demonstrated that four pluripotency factors (Oct4, Sox2, Klf4, and c-Myc) are sufficient to directly reprogram fibroblasts to other specific cells, including induced neural stem cells (iNSCs). Here, we show that mouse fibroblasts can be directly reprogrammed into midbrain dopaminergic neuronal progenitors (DPs) by temporal expression of the pluripotency factors and environment containing sonic hedgehog and fibroblast growth factor 8. Within thirteen days, self-renewing and functional induced DPs (iDPs) were generated. Interestingly, the inhibition of both Jak and Gsk3β notably enhanced the iDP reprogramming efficiency. We confirmed the functionality of the iDPs by showing that the dopaminergic neurons generated from iDPs express midbrain markers, release dopamine, and show typical electrophysiological profiles. Our results demonstrate that the pluripotency factors-mediated direct reprogramming is an invaluable strategy for supplying functional and proliferating iDPs and may be useful for other neural progenitors required for disease modeling and cell therapies for neurodegenerative disorders.
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea.
authors.forename: Han-Seop
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea; University of Science & Technology, 113 Gwahak-ro, Yuseong-gu, Daejeon 305-333, Republic of Korea.
authors.forename: Janghwan
authors.initials: J
authors.lastname: Kim
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea.
authors.forename: Yeonju
authors.initials: Y
authors.lastname: Jo
authors.affiliation: Laboratory for Brain Behavior and Therapeutics, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea.
authors.forename: Daejong
authors.initials: D
authors.lastname: Jeon
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea; University of Science & Technology, 113 Gwahak-ro, Yuseong-gu, Daejeon 305-333, Republic of Korea. Electronic address: june@kribb.re.kr.
authors.forename: Yee Sook
authors.initials: YS
authors.lastname: Cho
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D019070:Cell Lineage; D065150:Cellular Reprogramming / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000378:metabolism; D051524:Fibroblast Growth Factor 8 / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D053823:Hedgehog Proteins / Q000494:pharmacology; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C473711:Chir 99021; D053823:Hedgehog Proteins; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D011725:Pyridines; D011743:Pyrimidines; D014157:Transcription Factors; D051524:Fibroblast Growth Factor 8; D053612:Janus Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D004298:Dopamine