title: Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons.
abstract: Directed conversion of mature human cells, as from fibroblasts to neurons, is of potential clinical utility for neurological disease modeling as well as cell therapeutics. Here, we describe the efficient generation of human-induced neuronal (hiN) cells from adult skin fibroblasts of unaffected individuals and Alzheimer's patients, using virally transduced transcription regulators and extrinsic support factors. hiN cells from unaffected individuals display morphological, electrophysiological, and gene expression profiles that typify glutamatergic forebrain neurons and are competent to integrate functionally into the rodent CNS. hiN cells from familial Alzheimer disease (FAD) patients with presenilin-1 or -2 mutations exhibit altered processing and localization of amyloid precursor protein (APP) and increased production of Aβ, relative to the source patient fibroblasts or hiN cells from unaffected individuals. Together, our findings demonstrate directed conversion of human fibroblasts to a neuronal phenotype and reveal cell type-selective pathology in hiN cells derived from FAD patients.
authors.affiliation: Departments of Pathology, Cell Biology, and Neurology and Taub Institute, Columbia University, New York, NY 10032, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Qiang
authors.forename: Ryousuke
authors.initials: R
authors.lastname: Fujita
authors.forename: Toru
authors.initials: T
authors.lastname: Yamashita
authors.forename: Sergio
authors.initials: S
authors.lastname: Angulo
authors.forename: Herve
authors.initials: H
authors.lastname: Rhinn
authors.forename: David
authors.initials: D
authors.lastname: Rhee
authors.forename: Claudia
authors.initials: C
authors.lastname: Doege
authors.forename: Lily
authors.initials: L
authors.lastname: Chau
authors.forename: Laetitia
authors.initials: L
authors.lastname: Aubry
authors.forename: William B
authors.initials: WB
authors.lastname: Vanti
authors.forename: Herman
authors.initials: H
authors.lastname: Moreno
authors.forename: Asa
authors.initials: A
authors.lastname: Abeliovich
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D009474:Neurons / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism; D053766:Presenilin-2 / Q000378:metabolism; D044968:Regenerative Medicine / Q000379:methods*; D012867:Skin / Q000166:cytology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D053766:Presenilin-2