Myt1l induced direct reprogramming of pericytes into cholinergic neurons

• Published in: CNS neuroscience & therapeutics 2018-09, Vol.24 (9), p.801-809
• Main Authors: Liang, Xing‐Guang, Tan, Chao, Wang, Cheng‐Kun, Tao, Rong‐Rong, Huang, Yu‐Jie, Ma, Kui‐Fen, Fukunaga, Kohji, Huang, Ming‐Zhu, Han, Feng
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; ASCL1 protein; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cells, Cultured; Cellular Reprogramming - drug effects; Cellular Reprogramming - physiology; cholinergic neuron; Cholinergic Neurons - drug effects; Cholinergic Neurons - metabolism; Cognitive ability; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; human brain vascular pericytes; Humans; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - pharmacology; neurodegenerative disease; Neurodegenerative diseases; Neurons; Original; Pericytes; Pericytes - drug effects; Pericytes - metabolism; reprogramming; Somatic cells; Tlx3 protein; Transcription factors; Transcription Factors - biosynthesis; Transcription Factors - pharmacology
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.12821

Summary Objective The cholinergic deficit is thought to underlie progressed cognitive decline in Alzheimer Disease. The lineage reprogramming of somatic cells into cholinergic neurons may provide strategies toward cell‐based therapy of neurodegenerative diseases. Methods and results Here, we found that a combination of neuronal transcription factors, including Ascl1, Myt1l, Brn2, Tlx3, and miR124 (5Fs) were capable of directly converting human brain vascular pericytes (HBVPs) into cholinergic neuronal cells. Intriguingly, the inducible effect screening of reprogramming factors showed that a single reprogramming factor, Myt1l, induced cells to exhibit similarly positive staining for Tuj1, MAP2, ChAT, and VAChT upon lentivirus infection with the 5Fs after 30 days. HBVP‐converted neurons were rarely labeled even after long‐term incubation with BrdU staining, suggesting that induced neurons were directly converted from HBVPs rather than passing through a proliferative state. In addition, the overexpression of Myt1l induced the elevation of Ascl1, Brn2, and Ngn2 levels that contributed to reprogramming. Conclusions Our findings provided proof of the principle that cholinergic neurons could be produced from HBVPs by reprogramming factor‐mediated fate instruction. Myt1l was a critical mediator of induced neuron cell reprogramming. HBVPs represent another excellent alternative cell resource for cell‐based therapy to treat neurodegenerative disease.