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• W2885333501 abstract "Researchers studying neurological degenerative diseases, particularly spinal cord injury, have long sought a treatment to recreate the neuronal connections lost during the course of disease, but curative therapy remains elusive. The concept of regenerating neurons, however, opposes the traditional dogma that neurons are quiescent cells possessing minimal capacity for regeneration. But what if other cell types can be harnessed to act as, or even develop into, neurons? A new focus of research examining induced neuronal (iN) cells answers this question, and more importantly, may create a new direction for future treatment of neurological degenerative diseases. Previous evidence suggests that transient overexpression of a small number of transcription factors can induce neuronal differentiation without triggering cell division.1 Though, most recently an article published in Nature from Tsunemoto and colleagues2 from Scripps Institute and the University of California at San Diego expands upon these principles and demonstrates stronger evidence for the potential utility of iN cells as a medical therapy. The study details a series of experiments attempting firstly, to identify which combinations of transcription factors can induce fibroblast differentiation into neurons and secondly, to engineer these cells to express or repress certain genes and thus enabling researchers to predict their function. To assess that transcription factors possessed the ability to induce neuronal differentiation, lentiviral vectors with complementary DNA (cDNA) encoding nearly 600 transcription factor pairs were targeted to mouse embryonic fibroblasts (MEFs) for 2 wk. Expression of various neuronal markers was used as an indicator for successful induction (Figure). Next, electrophysiological properties of the iN cells were examined, as this function is essential in characterizing a neuron. Fluorescence-activated cell sorting (FACS) and RNA sequencing were then used to examine transcriptome similarity between iN cells and endogenous neurons. Following this genetic analysis, applied bioinformatics using ingenuity pathway analysis (IPA) and hypergeometric optimization of motif enrichment (HOMER) identified key transcriptional regulatory mechanisms within iN cells, comparing levels of gene expression to MEFs and endogenous neuronal populations. Single-cell RNA sequencing (scRNA-seq) was conducted to determine both the homogeneity of cells induced by a single pair of transcription factors and the heterogeneity of iN cells from different populations. Finally, patterns of coexpression between iN populations were analyzed to determine synergistic transcription factors essential for core neuronal differentiation and function.FIGURE.: Immunofluorescence of TUJ1+ iN cells demonstrating neuronal marker expression of tau-eGFP, MAP2, or Synapsin after induction via Neurog3/Pou1f1 transcription factor pairing. iN cells in red, neuronal markers in green, and cell nuclei in blue (DAPI). Reprinted by permission from Springer Nature: Nature, Diverse reprogramming codes for neuronal identity. Tsunemoto R, Lee S, Szucs A, et al.2 Copryight 2018.Of the 598 transcription factor pairs screened, 76 (12.7%) produced iN cells with neuronal morphologies. Interestingly, 5 subsets of iN cells produced by transcription factors not previously reported as neuron-inducing displayed resting membrane potentials and fired action potentials. Furthermore, these mouse transcription factors induced human embryonic fibroblast differentiation into human iN cells capable of firing action potentials, thus enabling future guidance of human cell reprogramming. FACS and RNA sequencing analysis determined that 3860 genes upregulated in iN cells compared to MEFs were associated with neuronal development and synaptic transmission and the 3467 downregulated genes played a role in cell division and immune function. Additionally, a mean genetic overlap of 78% was observed between iN cells and endogenous neurons. Taken together, these results demonstrate that iN cells acquired transcriptomes highly similar to endogenous neurons and allow for specific convergence on shared transcriptional regulators at the core of neuronal development. Further examination with IPA and HOMER analyses identified 39 and 48 transcriptional regulators, respectively, uncovering certain genes that served as either repressors or activators during reprogramming. ScRNA-seq determined that cells induced by the same transcription factors displayed relative homogeneity and importantly, different iN cell populations expressed various cell types (ie, ion channels or transmembrane proteins) depending on the transcription factors. Additionally, generation of iN cells with various neurotransmitter profiles was observed. These findings suggest that regulation of gene expression via certain transcription factors can potentially limit the iN cell population to a specific morphology and may therefore translate into future targeted therapies for disease. The findings of this study create a promising avenue for future applications in medicine, and particularly in neurosurgery. For patients with spinal cord injuries, use of mesenchymal stem cell therapy, cellular scaffolds, or a combination of both is a current focus.3 Engineering of iN cells with a specific neuronal morphology would likely augment these therapies, creating a highly specific milieu of neurons and glia required to support nerve regeneration. Similarly, iN cells expressing particular combinations of neurotransmitters and receptors could be induced to regenerate motor or sensory function, aiding in peripheral nerve disorders. Potential applications also include the brain, where targeted iN cells may repopulate eloquent areas following tumor resection, thus facilitating more complete tumor resection with fewer long-term complications. Expectations must be tempered though as iN cell differentiation models have yet to leave the laboratory, but an important takeaway remains—we are discovering unique ways of circumventing conventional wisdom. If neurons do not readily regenerate themselves, then perhaps we can engineer neurons ourselves. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article." @default.
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• W2885333501 date "2018-08-17" @default.
• W2885333501 modified "2023-10-18" @default.
• W2885333501 title "Engineered Neurons May Generate Future Therapy for Neurological Disease" @default.
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• W2885333501 doi "https://doi.org/10.1093/neuros/nyy299" @default.
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