Oct4-Induced Reprogramming Is Required for Adult Brain Neural Stem Cell Differentiation into Midbrain Dopaminergic Neurons
نویسندگان
چکیده
Neural stem cells (NSCs) lose their competency to generate region-specific neuronal populations at an early stage during embryonic brain development. Here we investigated whether epigenetic modifications can reverse the regional restriction of mouse adult brain subventricular zone (SVZ) NSCs. Using a variety of chemicals that interfere with DNA methylation and histone acetylation, we showed that such epigenetic modifications increased neuronal differentiation but did not enable specific regional patterning, such as midbrain dopaminergic (DA) neuron generation. Only after Oct-4 overexpression did adult NSCs acquire a pluripotent state that allowed differentiation into midbrain DA neurons. DA neurons derived from Oct4-reprogrammed NSCs improved behavioural motor deficits in a rat model of Parkinson's disease (PD) upon intrastriatal transplantation. Here we report for the first time the successful differentiation of SVZ adult NSCs into functional region-specific midbrain DA neurons, by means of Oct-4 induced pluripotency.
منابع مشابه
Direct lineage reprogramming of mouse fibroblasts to functional midbrain dopaminergic neuronal progenitors.
The direct lineage reprogramming of somatic cells to other lineages by defined factors has led to innovative cell-fate-change approaches for providing patient-specific cells. Recent reports have demonstrated that four pluripotency factors (Oct4, Sox2, Klf4, and c-Myc) are sufficient to directly reprogram fibroblasts to other specific cells, including induced neural stem cells (iNSCs). Here, we ...
متن کاملReprogramming by cytosolic extract of human embryonic stem cells improves dopaminergic differentiation potential of human adipose tissue-derived stem cells
The extract of pluripotent stem cells induces dedifferentiation of somatic cells with restricted plasticity. In this study, we used the extract of human embryonic stem cells (hESC) to dedifferentiate adipose tissue-derived stem cells (ADSCs) and examined the impact of this reprogramming event on dopaminergic differentiation of the cells. For this purpose, cytoplasmic extract of ESCs was prepare...
متن کاملNeurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease.
The long-term goal of nuclear transfer or alternative reprogramming approaches is to create patient-specific donor cells for transplantation therapy, avoiding immunorejection, a major complication in current transplantation medicine. It was recently shown that the four transcription factors Oct4, Sox2, Klf4, and c-Myc induce pluripotency in mouse fibroblasts. However, the therapeutic potential ...
متن کاملIsolation and Differentiation of Neural Stem/Progenitor Cells From Subventricular Zone of One Adult Rat
Introduction: In adult mammalian brain, neural stem cells are isolated from both the dentate gyrus and subventricular zone. This study aimed to isolate neural stem cells from adult rat subventricular zone and differentiate them into neurons and astrocytes. Methods: In this study, the whole brain was removed after full anesthesia and creating cervical dislocation. Under a microscope, subv...
متن کاملSelective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion
Degeneration of midbrain dopaminergic (DA) neurons is a key pathological event of Parkinson's disease (PD). Limited adult dopaminergic neurogenesis has led to novel therapeutic strategies such as transplantation of dopaminergic precursors (DPs). However, this strategy is currently restrained by a lack of cell source, the tendency for the DPs to become a glial-restricted state, and the tumor for...
متن کامل