Biomedicines
Department of Precision Medicine, Graduate School of Basic Medical Science (GSBMS), Institute for Antimicrobial Resistance Research and Therapeutics, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
Published: April 2022
Astrocyte-to-neuron reprogramming is a promising therapeutic approach for treatment of neurodegenerative diseases. The use of small molecules as an alternative to the virus-mediated ectopic expression of lineage-specific transcription factors negates the tumorigenic risk associated with viral genetic manipulation and uncontrolled differentiation of stem cells. However, because previously developed methods for small-molecule reprogramming of astrocytes to neurons are multistep, complex, and lengthy, their applications in biomedicine, including clinical treatment, are limited. Therefore, our objective in this study was to develop a novel chemical-based approach to the cellular reprogramming of astrocytes into neurons with high efficiency and low complexity. To accomplish that, we used C8-D1a, a mouse astrocyte cell line, to assess the role of small molecules in reprogramming protocols that otherwise suffer from inconsistencies caused by variations in donor of the primary cell. We developed a new protocol by which a chemical mixture formulated with Y26732, DAPT, RepSox, CHIR99021, ruxolitinib, and SAG rapidly and efficiently induced the neural reprogramming of astrocytes in four days, with a conversion efficiency of 82 ± 6%. Upon exposure to the maturation medium, those reprogrammed cells acquired a glutaminergic phenotype over the next eleven days. We also demonstrated the neuronal functionality of the induced cells by confirming KCL-induced calcium flux.
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http://dx.doi.org/10.3390/biomedicines10040928 | DOI Listing |
Int J Mol Sci
January 2025
Department of Biosciences, Biotechnologies and Environment, University of Bari, 70125 Bari, Italy.
Neurodegenerative diseases are characterized by progressive loss of neurons and persistent inflammation. Neurons are terminally differentiated cells, and lost neurons cannot be replaced since neurogenesis is restricted to only two neurogenic niches in the adult brain, whose neurogenic potential decreases with age. In this regard, the astrocytes reprogramming into neurons may represent a promising strategy for restoring the lost neurons and rebuilding neural circuits.
View Article and Find Full Text PDFNeuroscience
January 2025
Biochemistry Department and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
In this special issue to celebrate the 30th anniversary of the Uruguayan Society for Neuroscience (SNU), we find it pertinent to highlight that research on glial cells in Uruguay began almost alongside the history of SNU and contributed to the understanding of neuron-glia interactions within the international scientific community. Glial cells, particularly astrocytes, traditionally regarded as supportive components in the central nervous system (CNS), undergo notable morphological and functional alterations in response to neuronal damage, a phenomenon referred to as glial reactivity. Among the myriad functions of astrocytes, metabolic support holds significant relevance for neuronal function, given the high energy demand of the nervous system.
View Article and Find Full Text PDFFree Radic Biol Med
January 2025
Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China. Electronic address:
Astrocytes are critical for maintaining neuronal activity. Activation of astrocytes, occurs within minutes from ischemic stroke onset due to ischemic causes and subsequent inflammatory damage. Activated astrocytes, also known as reactive astrocytes, are divided into two different phenotypes: A1 (pro-inflammatory) and A2 (anti-inflammatory) astrocytes.
View Article and Find Full Text PDFCell Rep
January 2025
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:
Neurogenic microRNAs 9/9 and 124 (miR-9/9-124) drive the direct reprogramming of human fibroblasts into neurons with the initiation of the fate erasure of fibroblasts. However, whether the miR-9/9-124 fate erasure logic extends to the neuronal conversion of other somatic cell types remains unknown. Here, we uncover that miR-9/9-124 induces neuronal conversion of multiple cell types: dura fibroblasts, astrocytes, smooth muscle cells, and pericytes.
View Article and Find Full Text PDFSci Rep
December 2024
Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
Astrocyte to neuron reprogramming has been performed using viral delivery of neurogenic transcription factors in GFAP expressing cells. Recent reports of off-target expression in cortical neurons following adeno-associated virus (AAV) transduction to deliver the neurogenic factors have confounded our understanding of the efficacy of direct cellular reprogramming. To shed light on potential mechanisms that may underlie the neuronal off-target expression of GFAP promoter driven expression of neurogenic factors in neurons, two regionally distinct cortices were compared-the motor cortex (MC) and medial prefrontal cortex (mPFC)-and investigated: (1) the regional tropism and astrocyte transduction with an AAV5-GFAP vector, (2) the expression of Gfap in MC and mPFC neurons; and (3) material transfer between astrocytes and neurons.
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