TY - JOUR
T1 - Myt1l induced direct reprogramming of pericytes into cholinergic neurons
AU - Liang, Xing Guang
AU - Tan, Chao
AU - Wang, Cheng Kun
AU - Tao, Rong Rong
AU - Huang, Yu Jie
AU - Ma, Kui Fen
AU - Fukunaga, Kohji
AU - Huang, Ming Zhu
AU - Han, Feng
N1 - Funding Information:
Project of Science and Technology Department of Zhejiang Province, Grant/ Award Number: 2017C33053; National Natural Science Foundation of China, Grant/ Award Number: 81503048; Natural Science Foundation of Zhejiang Province, Grant/ Award Number: LY15H030007 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. This work was supported in part by Projects of National Natural Science Foundation of China (81503048), Science and Technology Department of Zhejiang Province (2017C33053), Natural Science Foundation of Zhejiang Province (LY15H030007).
Funding Information:
This work was supported in part by Projects of National Natural Science Foundation of China (81503048), Science and Technology Department of Zhejiang Province (2017C33053), Natural Science Foundation of Zhejiang Province (LY15H030007).
Funding Information:
Project of Science and Technology Department of Zhejiang Province, Grant/ Award Number: 2017C33053; National Natural Science Foundation of China, Grant/ Award Number: 81503048; Natural Science Foundation of Zhejiang Province, Grant/ Award Number: LY15H030007
Publisher Copyright:
© 2018 John Wiley & Sons Ltd.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Cholinergic neuron
KW - Human brain vascular pericytes
KW - Neurodegenerative disease
KW - Reprogramming
KW - Transcription factors
UR - http://www.scopus.com/inward/record.url?scp=85042120501&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85042120501&partnerID=8YFLogxK
U2 - 10.1111/cns.12821
DO - 10.1111/cns.12821
M3 - Article
C2 - 29453933
AN - SCOPUS:85042120501
VL - 24
SP - 801
EP - 809
JO - CNS Neuroscience and Therapeutics
JF - CNS Neuroscience and Therapeutics
SN - 1755-5930
IS - 9
ER -