title: Multilineage-differentiating stress-enduring (Muse) cells are a primary source of induced pluripotent stem cells in human fibroblasts.
abstract: The stochastic and elite models have been proposed for the mechanism of induced pluripotent stem (iPS) cell generation. In this study we report a system that supports the elite model. We previously identified multilineage-differentiating stress-enduring (Muse) cells in human dermal fibroblasts that are characterized by stress tolerance, expression of pluripotency markers, self-renewal, and the ability to differentiate into endodermal-, mesodermal-, and ectodermal-lineage cells from a single cell. They can be isolated as stage-specific embryonic antigen-3/CD105 double-positive cells. When human fibroblasts were separated into Muse and non-Muse cells and transduced with Oct3/4, Sox2, Klf4, and c-Myc, iPS cells were generated exclusively from Muse cells but not from non-Muse cells. Although some colonies were formed from non-Muse cells, they were unlike iPS cells. Furthermore, epigenetic alterations were not seen, and some of the major pluripotency markers were not expressed for the entire period during iPS cell generation. These findings were confirmed further using cells transduced with a single polycistronic virus vector encoding all four factors. The results demonstrate that in adult human fibroblasts a subset of preexisting adult stem cells whose properties are similar in some respects to those of iPS cells selectively become iPS cells, but the remaining cells make no contribution to the generation of iPS cells. Therefore this system seems to fit the elite model rather than the stochastic model.
authors.affiliation: Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Wakao
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kitada
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Kuroda
authors.forename: Taeko
authors.initials: T
authors.lastname: Shigemoto
authors.forename: Dai
authors.initials: D
authors.lastname: Matsuse
authors.forename: Hideo
authors.initials: H
authors.lastname: Akashi
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Tanimura
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Tsuchiyama
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Makoto
authors.initials: M
authors.lastname: Goda
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fujiyoshi
authors.forename: Mari
authors.initials: M
authors.lastname: Dezawa
mesh_terms: D000222:Adaptation, Physiological; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology; D000071063:Endoglin; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D055746:Stage-Specific Embryonic Antigens / Q000378:metabolism; D013312:Stress, Physiological; D014162:Transfection
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D015295:Antigens, Tumor-Associated, Carbohydrate; C064206:ENG protein, human; D000071063:Endoglin; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D011956:Receptors, Cell Surface; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D055746:Stage-Specific Embryonic Antigens; C519803:TRA-1-81 antigen, human; C052924:stage-specific embryonic antigen-3