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Reprogramming of adult human dermal fibroblasts to induced dorsal forebrain precursor cells maintains aging signatures. | LitMetric

Reprogramming of adult human dermal fibroblasts to induced dorsal forebrain precursor cells maintains aging signatures.

Front Cell Neurosci

Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Published: January 2023

AI Article Synopsis

  • * The authors created a method using chemically modified mRNA to convert adult skin cells into a specific type of brain precursor cells that maintain age-related characteristics, allowing for better modeling of diseases.
  • * Their findings show that this direct reprogramming approach retains key aging biomarkers while altering neuronal morphology with donor age, offering new insights into neurodegenerative diseases and potential therapeutic targets.

Article Abstract

With the increase in aging populations around the world, the development of human cell models to study neurodegenerative disease is crucial. A major limitation in using induced pluripotent stem cell (hiPSC) technology to model diseases of aging is that reprogramming fibroblasts to a pluripotent stem cell state erases age-associated features. The resulting cells show behaviors of an embryonic stage exhibiting longer telomeres, reduced oxidative stress, and mitochondrial rejuvenation, as well as epigenetic modifications, loss of abnormal nuclear morphologies, and age-associated features. We have developed a protocol utilizing stable, non-immunogenic chemically modified mRNA (cmRNA) to convert adult human dermal fibroblasts (HDFs) to human induced dorsal forebrain precursor (hiDFP) cells, which can subsequently be differentiated into cortical neurons. Analyzing an array of aging biomarkers, we demonstrate for the first time the effect of direct-to-hiDFP reprogramming on cellular age. We confirm direct-to-hiDFP reprogramming does not affect telomere length or the expression of key aging markers. However, while direct-to-hiDFP reprogramming does not affect senescence-associated β-galactosidase activity, it enhances the level of mitochondrial reactive oxygen species and the amount of DNA methylation compared to HDFs. Interestingly, following neuronal differentiation of hiDFPs we observed an increase in cell soma size as well as neurite number, length, and branching with increasing donor age suggesting that neuronal morphology is altered with age. We propose direct-to-hiDFP reprogramming provides a strategy for modeling age-associated neurodegenerative diseases allowing the persistence of age-associated signatures not seen in hiPSC-derived cultures, thereby facilitating our understanding of neurodegenerative disease and identification of therapeutic targets.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9922835PMC
http://dx.doi.org/10.3389/fncel.2023.1003188DOI Listing

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