title: Transdifferentiation of mesenchymal stem cells-derived adipogenic-differentiated cells into osteogenic- or chondrogenic-differentiated cells proceeds via dedifferentiation and have a correlation with cell cycle arresting and driving genes.
abstract: It is generally accepted that after differentiation bone marrow mesenchymal stem cells (MSC) become lineage restricted and unipotent in an irreversible manner. However, current results imply that even terminally differentiated cells transdifferentiate across lineage boundaries and therefore act as a progenitor cells for other lineages. This leads to the questions that whether transdifferentiation occurs via direct cell-to-cell conversion or dedifferentiation to a progenitor cells and subsequent differentiation, and whether MSC potency decreases or increases during differentiation. To address these questions, MSC were differentiated into adipogenic lineage cells, followed by dedifferentiation. The process of dedifferentiation was also confirmed by single cell clonal analysis. Finally the dedifferentiated cells were used for adipogenesis, osteogenesis and chondrogenesis. Histology, FACS, qPCR and GeneChip analyses of undifferentiated MSC, adipogenic-differentiated and dedifferentiated cells were performed. Interestingly, gene profiling and bioinformatics demonstrated that upregulation (DHCR24, G0S2, MAP2K6, SESN3) and downregulation (DST, KAT2, MLL5, RB1, SMAD3, ZAK) of distinct genes have an association with cell cycle arrest in adipogenic-differentiated cells and perhaps narrow down the lineage potency. However, the upregulation (CCND1, CHEK, HGF, HMGA2, SMAD3) and downregulation (CCPG1, RASSF4, RGS2) of these genes have an association with cell cycle progression and maybe motivate dedifferentiation of adipogenic-differentiated cells. We found that dedifferentiated cells have a multilineage potency comparable to MSC, and also observed the associative role of proliferation genes with cell cycle arrest and progression. Concluded, our results indicate that transdifferentiation of adipogenic-differentiated cells into osteogenic- or chondrogenic-differentiated cells proceeds via dedifferentiation and correlates with cell cycle arresting and deriving genes. Regarding clinical use, the knowledge of potency and underlying mechanisms are prerequisites.
authors: Tissue Engineering Laboratory & Berlin-Brandenburg Center for Regenerative Therapies, Dept. of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany. mujib.ullah@charite.de
authors: Mujib
authors: M
authors: Ullah
authors: Stefan
authors: S
authors: Stich
authors: Michael
authors: M
authors: Notter
authors: Jan
authors: J
authors: Eucker
authors: Michael
authors: M
authors: Sittinger
authors: Jochen
authors: J
authors: Ringe
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D001854:Bone Marrow Cells / Q000166:cytology; D059447:Cell Cycle Checkpoints / Q000235:genetics; D054337:Cell Dedifferentiation; D002454:Cell Differentiation; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D020219:Chondrogenesis / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D020411:Oligonucleotide Array Sequence Analysis; D010012:Osteogenesis / Q000235:genetics; D013234:Stem Cells / Q000166:cytology; D015854:Up-Regulation