title: Tumorigenicity analysis of heterogeneous dental stem cells and its self-modification for chromosome instability.
abstract: Heterogeneity demonstrates that stem cells are constituted by several sub-clones in various differentiation states. The heterogeneous state is maintained by cross-talk among sub-clones, thereby ensuring stem cell adaption. In this study, we investigated the roles of heterogeneity on genetic stability. Three sub-clones (DF2, DF8 and DF18) were isolated from heterogeneous dental stem cells (DSCs), and were proved to be chromosome instability (CIN) after long term expansion. Cell apoptosis were not detected in sub-clones, which exhibited strong tumorigenesis tendency, coupled with weak expression of p53 and aberrant ultra-structure. However, 3 sub-clones did not overexpress tumor related markers or induce tumorigenesis in vivo. The mixed-culture study suggested that 3-clone-mixed culturing cells (DF1) presented apparent decrease in the ratio of aneuploidy. The screening experiment further proved that 3 sub-clones functioned separately in this modification procedure but only mixed culturing all 3 sub-clones, simulated heterogeneous microenvironment, could achieve complete modification. Additionally, osteogenesis capability of 3 sub-clones was partially influenced by CIN while DSCs still kept stronger osteogenesis than sub-clones. These results suggested aberrant sub-clones isolated from heterogeneous DSCs were not tumorigenesis and could modify CIN by cross-talk among themselves, indicating that the heterogeneity played a key role in maintaining genetic stability and differentiation capability in dental stem cells.
authors: a National Engineering Laboratory for Oral Regenerative Medicine; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|b State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|c Department of Oral and Maxillofacial Surgery ; West China School of Stomatology; Sichuan University ; Chengdu , China.
authors: Zhaosong
authors: Z
authors: Meng
authors: a National Engineering Laboratory for Oral Regenerative Medicine; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|b State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.
authors: Guoqing
authors: G
authors: Chen
authors: a National Engineering Laboratory for Oral Regenerative Medicine; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|b State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|c Department of Oral and Maxillofacial Surgery ; West China School of Stomatology; Sichuan University ; Chengdu , China.
authors: Jinlong
authors: J
authors: Chen
authors: a National Engineering Laboratory for Oral Regenerative Medicine; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|b State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|c Department of Oral and Maxillofacial Surgery ; West China School of Stomatology; Sichuan University ; Chengdu , China.
authors: Bo
authors: B
authors: Yang
authors: a National Engineering Laboratory for Oral Regenerative Medicine; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|b State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.
authors: Mei
authors: M
authors: Yu
authors: a National Engineering Laboratory for Oral Regenerative Medicine; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|b State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.
authors: Lian
authors: L
authors: Feng
authors: a National Engineering Laboratory for Oral Regenerative Medicine; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|b State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.
authors: Zongting
authors: Z
authors: Jiang
authors: a National Engineering Laboratory for Oral Regenerative Medicine; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|b State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|d Department of Pedodontics ; West China School of Stomatology; Sichuan University ; Chengdu , China.
authors: Weihua
authors: W
authors: Guo
authors: a National Engineering Laboratory for Oral Regenerative Medicine; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|b State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University ; Chengdu , China.|c Department of Oral and Maxillofacial Surgery ; West China School of Stomatology; Sichuan University ; Chengdu , China.
authors: Weidong
authors: W
authors: Tian
mesh_terms: D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D043171:Chromosomal Instability; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D003795:Dental Sac / Q000166:cytology; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D059785:Karyotype; D064246:Mad2 Proteins / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000648:ultrastructure; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis; D010641:Phenotype; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050687:E2F1 Transcription Factor; C493755:E2f1 protein, rat; D064246:Mad2 Proteins; D016159:Tumor Suppressor Protein p53
keywords: CIN; DFSCs; aneuploidy; cell-based therapy; heterogeneity