Reprogramming rat astrocytes into neurons using small molecules for cell replacement following intracerebral hemorrhage

Astrocytes are promising source cells to replace neurons lost disease owing a shared lineage and capacities for dedifferentiation proliferation under pathological conditions. Reprogramming of astrocytes has been achieved by transcription factor modulation, but reprogramming in vitro or vivo using small‐molecule drugs may have several advantages clinical application. For instance, small molecules can be extensively characterized efficacy, toxicity, tumorigenicity vitro; induce rapid initiation subsequent reversal transdifferentiation upon withdrawal, obviate the need exogenous gene transfection. Here we report new astrocyte–neuron strategy combination (0.5 mM valproic acid, 1 μM RepSox, 3 CHIR99021, 2 I‐BET151, 10 ISX‐9, forskolin). Treatment with this drug gradually reduced expression levels astroglial marker proteins (glial fibrillary acidic protein S100), transiently enhanced neuronal progenitor doublecortin, subsequently elevated mature NeuN primary astrocyte cultures. These changes were accompanied transition neuron‐like morphological phenotype multiple factors. Further, induced astrocyte‐to‐neuron culture model intracerebral hemorrhage (ICH) upregulated many transdifferentiation‐associated signaling ICH rats. In culture, also model‐associated oxidative stress, apoptosis, pro‐inflammatory cytokine production. Neurons derived from adult Sprague–Dawley rats demonstrated long‐term survival maintenance phenotype. This small‐molecule‐induced method replacement therapy.