Abstract
Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. We hypothesized that combinatorial expression of chondrocyte-specific transcription factors could directly convert human placental cells into chondrocytes. Starting from a pool of candidate genes, we identified a combination of only five genes (5F pool)-BCL6, T (also called BRACHYURY), c-MYC, MITF, and BAF60C (also called SMARCD3)-that rapidly and efficiently convert postnatal human chorion and decidual cells into chondrocytes. The cells generated expressed multiple cartilage-specific genes, such as Collagen type II α1, LINK PROTEIN-1, and AGGRECAN, and exhibited characteristics of cartilage both in vivo and in vitro. Expression of the endogenous genes for T and MITF was initiated, implying that the cell conversion is due to not only the forced expression of the transgenes, but also to cellular reprogramming by the transgenes. This direct conversion system from noncartilage tissue to cartilaginous tissue is a substantial advance toward understanding cartilage development, cell-based therapy, and oncogenesis of chondrocytes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Blotting, Western
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Cartilage / cytology*
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Cartilage / metabolism
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Cell Dedifferentiation*
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Cells, Cultured
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Chondrocytes / cytology*
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Chondrocytes / metabolism
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Chondrogenesis / genetics
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Chorion / cytology
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Chorion / metabolism
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Chromosomal Proteins, Non-Histone
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Decidua / cytology
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Decidua / metabolism
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Female
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Fetal Proteins / genetics
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Fetal Proteins / metabolism
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Gene Expression Profiling
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Humans
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Induced Pluripotent Stem Cells / cytology
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Induced Pluripotent Stem Cells / metabolism
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Karyotyping
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Mice
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Microphthalmia-Associated Transcription Factor / genetics
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Microphthalmia-Associated Transcription Factor / metabolism
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Placenta / cytology*
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Placenta / metabolism
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Pregnancy
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Proto-Oncogene Proteins c-bcl-6
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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RNA Interference
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transfection
Substances
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BCL6 protein, human
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Chromosomal Proteins, Non-Histone
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DNA-Binding Proteins
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Fetal Proteins
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MITF protein, human
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MYC protein, human
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Microphthalmia-Associated Transcription Factor
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Proto-Oncogene Proteins c-bcl-6
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Proto-Oncogene Proteins c-myc
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SMARCD3 protein, human
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T-Box Domain Proteins
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Transcription Factors
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Brachyury protein