Repression of COUP-TFI Improves Bone Marrow-Derived Mesenchymal Stem Cell Differentiation into Insulin-Producing Cells
| Autor: | Rui Wang, Hongxin Lang, Xuewen Lin, Xiao-Hang Li, Dianbao Zhang, Xiaoyu Liu, Xining Pang, Tao Zhang, Feng Zhao |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Cellular differentiation Biology stem cell transplantation 03 medical and health sciences Drug Discovery medicine Transcription factor mesenchymal stem cells diabetes Insulin Mesenchymal stem cell lcsh:RM1-950 differentiation Molecular biology siRNAs Cell biology Transplantation 030104 developmental biology medicine.anatomical_structure lcsh:Therapeutics. Pharmacology Molecular Medicine Original Article Mesenchymal stem cell differentiation Bone marrow Stem cell |
| Zdroj: | Molecular Therapy: Nucleic Acids, Vol 8, Iss, Pp 220-231 (2017) Molecular Therapy. Nucleic Acids |
| ISSN: | 2162-2531 |
| Popis: | Identifying molecular mechanisms that regulate insulin expression in bone marrow-derived mesenchymal stem cells (bmMSCs) can provide clues on how to stimulate the differentiation of bmMSCs into insulin-producing cells (IPCs), which can be used as a therapeutic approach against type 1 diabetes (T1D). As repression factors may inhibit differentiation, the efficiency of this process is insufficient for cell transplantation. In this study, we used the mouse insulin 2 (Ins2) promoter sequence and performed a DNA affinity precipitation assay combined with liquid chromatography-mass spectrometry to identify the transcription factor, chicken ovalbumin upstream promoter transcriptional factor I (COUP-TFI). Functionally, bmMSCs were reprogrammed into IPCs via COUP-TFI suppression and MafA overexpression. The differentiated cells expressed higher levels of genes specific for islet endocrine cells, and they released C-peptide and insulin in response to glucose stimulation. Transplantation of IPCs into streptozotocin-induced diabetic mice caused a reduction in hyperglycemia. Mechanistically, COUP-TFI bound to the DR1 (direct repeats with 1 spacer) element in the Ins2 promoter, thereby negatively regulating promoter activity. Taken together, the data provide a novel mechanism by which COUP-TFI acts as a negative regulator in the Ins2 promoter. The differentiation of bmMSCs into IPCs could be improved by knockdown of COUP-TFI, which may provide a novel stem cell-based therapy for T1D. Keywords: siRNAs, differentiation, stem cell transplantation, diabetes, mesenchymal stem cells |
| Databáze: | OpenAIRE |
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