Pericyte-to-neuron reprogramming via unfolding of a neural stem cell-like program

Ectopic expression of defined transcription factors can force direct cell fate conversion from one lineage to another in the absence of cell division. Several transcription factor cocktails have enabled successful reprogramming of various somatic cell types into induced neurons (iNs) of distinct neurotransmitter phenotype. However, the nature of the intermediate states that drive the reprogramming trajectory towards distinct iN types is largely unknown. Here we show that successful direct reprogramming of adult human brain pericytes into functional iNs by Ascl1 and Sox2 (AS) encompasses transient activation of a neural stem cell-like gene expression program that precedes bifurcation into distinct neuronal lineages. Intriguingly, during this transient state key signaling components relevant for neural induction and neural stem cell maintenance are regulated and functionally contribute to iN reprogramming and maturation. Thus, AS-mediated reprogramming into a broad spectrum of iN types involves the unfolding of a developmental program via neural stem cell-like intermediates. Overall design: Single-cell transcriptomes from multiple time points and conditions during direct conversion of human pericytes into induced pericytes through the overexpression of defined factors. Please note that [1] the *ctrl samples represent mock-transfected cells (analyzed along side of the transfected cells) [2] The cell type (for each sample) is provided as 'pericytes or pericyte-derived induced neuronal cells' (as they are in a differentiation continuum from pericytes to neurons due to the treatment protocol) with the combination of 'genotype/variation' and 'time point' information.

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Karow M, Camp JG, Falk S, Gerber T, Pataskar A, Gac-Santel M, Kageyama J, Brazovskaja A, Garding A, Fan W, Riedemann T, Casamassa A, Smiyakin A, Schichor C, Götz M, Tiwari VK, Treutlein B, Berninger B