Myt1l induced direct reprogramming of pericytes into cholinergic neurons

Objective: The cholinergic deficit is thought to underlie progressed cognitive decline inAlzheimer Disease. The lineage reprogramming of somatic cells into cholinergic neuronsmay provide strategies toward cell-based therapy of neurodegenerative diseases.Methods and results: Here, we found that a combination of neuronal transcriptionfactors, including Ascl1, Myt1l, Brn2, Tlx3, and miR124 (5Fs) were capable of directlyconverting human brain vascular pericytes (HBVPs) into cholinergic neuronal cells.Intriguingly, the inducible effect screening of reprogramming factors showed that asingle reprogramming factor, Myt1l, induced cells to exhibit similarly positive stainingfor Tuj1, MAP2, ChAT, and VAChT upon lentivirus infection with the 5Fs after 30 days.HBVP-convertedneurons were rarely labeled even after long-termincubation withBrdU staining, suggesting that induced neurons were directly converted from HBVPsrather than passing through a proliferative state. In addition, the overexpression ofMyt1l induced the elevation of Ascl1, Brn2, and Ngn2 levels that contributed toreprogramming.Conclusions: Our findings provided proof of the principle that cholinergic neuronscould be produced from HBVPs by reprogramming factor-mediatedfate instruction.Myt1l was a critical mediator of induced neuron cell reprogramming. HBVPs representanother excellent alternative cell resource for cell-basedtherapy to treat neurodegenerativedisease.