In vitro generation of mature midbrain-type dopamine neurons by adjusting exogenous Nurr1 and Foxa2 expressions to their physiologic patterns
| Autor: | Sang-Hun Lee, Jae Jin Song, Parvin Valiulahi, Lesly Puspita, Jae-Won Shim, Taeho Kim |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Cellular differentiation Clinical Biochemistry Genetic Vectors Biology Biochemistry Rats Sprague-Dawley 03 medical and health sciences Neural Stem Cells Dopamine Mesencephalon Precursor cell Nuclear Receptor Subfamily 4 Group A Member 2 medicine Animals Humans Transgenes Molecular Biology Cells Cultured Dopaminergic Neurons HEK 293 cells Neural stem cell Cell biology Rats Transplantation 030104 developmental biology medicine.anatomical_structure HEK293 Cells Immunology Hepatocyte Nuclear Factor 3-beta Molecular Medicine Original Article Neuron Stem cell medicine.drug Stem Cell Transplantation |
| Zdroj: | Experimental & Molecular Medicine |
| ISSN: | 2092-6413 1226-3613 |
| Popis: | Developmental information aids stem cell biologists in producing tissue-specific cells. Recapitulation of the developmental profile of a specific cell type in an in vitro stem cell system provides a strategy for manipulating cell-fate choice during the differentiation process. Nurr1 and Foxa2 are potential candidates for genetic engineering to generate midbrain-type dopamine (DA) neurons for experimental and therapeutic applications in Parkinson’s disease (PD), as forced expression of these genes in neural stem/precursor cells (NPCs) yields cells with a complete battery of midbrain DA neuron-specific genes. However, simple overexpression without considering their expression pattern in the developing midbrain tends to generate DA cells without adequate neuronal maturation and long-term maintenance of their phenotype in vitro and in vivo after transplantation. We here show that the physiological levels and timing of Nurr1 and Foxa2 expression can be replicated in NPCs by choosing the right vectors and promoters. Controlled expression combined with a strategy for transgene expression maintenance induced generation of fully mature midbrain-type DA neurons. These findings demonstrate the feasibility of cellular engineering for artificial cell-fate specification. Neural stem cells can be made into fully mature dopamine-producing neurons through the controlled expression of two proteins, FOXA2 and NUUR1. This strategy has therapeutic potential for treating Parkinson's disease, a condition characterized by the loss of this type of neurons. A team in South Korea led by Jae-won Shim from Soonchunhyang University and Sang-Hun Lee from Hanyang University engineered stem cells derived from the brains of rat embryos to express two proteins involved in dopamine neuron development. The researchers fine-tuned the activity levels and timing of the proteins to closely match the patterns found naturally in the rat brain and coaxed the stem cells to form functional dopamine neurons. Activation of a particular signaling pathway enabled long-term expression of the two proteins, which boosted neuronal yield and survival. |
| Databáze: | OpenAIRE |
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