Induced neural progenitor cells abundantly secrete extracellular vesicles and promote the proliferation of neural progenitors via extracellular signal–regulated kinase pathways

Yizhao Ma; Kaizhe Wang; Jiabin Pan; Zhaohuan Fan; Changhai Tian; Xiaobei Deng; Kangmu Ma; Xiaohuan Xia; Yunlong Huang; Jialin C. Zheng

doi:10.1016/j.nbd.2018.12.003

Induced neural progenitor cells abundantly secrete extracellular vesicles and promote the proliferation of neural progenitors via extracellular signal–regulated kinase pathways

Yizhao Ma, Kaizhe Wang, Jiabin Pan, Zhaohuan Fan, Changhai Tian, Xiaobei Deng, Kangmu Ma, Xiaohuan Xia, Yunlong Huang, Jialin C. Zheng

Toxicology and Cancer Biology

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

Neural stem/progenitor cells (NPCs) are known to have potent therapeutic effects in neurological disorders through the secretion of extracellular vesicles (EVs). Despite the therapeutic potentials, the numbers of NPCs are limited in the brain, curbing the further use of EVs in the disease treatment. To overcome the limitation of NPC numbers, we used a three transcription factor (Brn2, Sox2, and Foxg1) somatic reprogramming approach to generate induced NPCs (iNPCs) from mouse fibroblasts and astrocytes. The resulting iNPCs released significantly higher numbers of EVs compared with wild-type NPCs (WT-NPCs). Furthermore, iNPCs-derived EVs (iNPC-EVs) promoted NPC function by increasing the proliferative potentials of WT-NPCs. Characterizations of EV contents through proteomics analysis revealed that iNPC-EVs contained higher levels of growth factor-associated proteins that were predicted to activate the down-stream extracellular signal-regulated kinase (ERK) pathways. As expected, the proliferative effects of iNPC-derived EVs on WT-NPCs can be blocked by an ERK pathway inhibitor. Our data suggest potent therapeutic effects of iNPC-derived EVs through the promotion of NPC proliferation, release of growth factors, and activation of ERK pathways. These studies will help develop highly efficient cell-free therapeutic strategies for the treatment of neurological diseases.

Original language	English
Pages (from-to)	322-334
Number of pages	13
Journal	Neurobiology of Disease
Volume	124
DOIs	https://doi.org/10.1016/j.nbd.2018.12.003
State	Published - Apr 2019

Bibliographical note

Funding Information:
This work was supported in part by research grants from the National Basic Research Program of China (973 Program Grant No. 2014CB965001 to JZ), Innovative Research Groups of the National Natural Science Foundation of China (# 81221001 to JZ), and Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (# 81329002 to JZ), the National Institutes of Health : 1R01NS097195-01 (JZ). We thank Dr. Chao Lin (Tongji University, Shanghai, China) for the assistance with the DLS. We thank Dr. Bin Li (Shanghai Institute of Applied Physics, Chinese Academy of Science) for providing Nanosight NS300. We thank Lenal Bottoms and Justin Peer for proofreading the manuscript.

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

Cellular reprogramming
ERK pathways
Extracellular vesicles
Growth factors
Neural progenitor cells
Proliferation

ASJC Scopus subject areas

Neurology

Access to Document

10.1016/j.nbd.2018.12.003

Cite this

@article{cd1f0f5555ef4adf92be9568d6deab16,

title = "Induced neural progenitor cells abundantly secrete extracellular vesicles and promote the proliferation of neural progenitors via extracellular signal–regulated kinase pathways",

abstract = "Neural stem/progenitor cells (NPCs) are known to have potent therapeutic effects in neurological disorders through the secretion of extracellular vesicles (EVs). Despite the therapeutic potentials, the numbers of NPCs are limited in the brain, curbing the further use of EVs in the disease treatment. To overcome the limitation of NPC numbers, we used a three transcription factor (Brn2, Sox2, and Foxg1) somatic reprogramming approach to generate induced NPCs (iNPCs) from mouse fibroblasts and astrocytes. The resulting iNPCs released significantly higher numbers of EVs compared with wild-type NPCs (WT-NPCs). Furthermore, iNPCs-derived EVs (iNPC-EVs) promoted NPC function by increasing the proliferative potentials of WT-NPCs. Characterizations of EV contents through proteomics analysis revealed that iNPC-EVs contained higher levels of growth factor-associated proteins that were predicted to activate the down-stream extracellular signal-regulated kinase (ERK) pathways. As expected, the proliferative effects of iNPC-derived EVs on WT-NPCs can be blocked by an ERK pathway inhibitor. Our data suggest potent therapeutic effects of iNPC-derived EVs through the promotion of NPC proliferation, release of growth factors, and activation of ERK pathways. These studies will help develop highly efficient cell-free therapeutic strategies for the treatment of neurological diseases.",

keywords = "Cellular reprogramming, ERK pathways, Extracellular vesicles, Growth factors, Neural progenitor cells, Proliferation",

author = "Yizhao Ma and Kaizhe Wang and Jiabin Pan and Zhaohuan Fan and Changhai Tian and Xiaobei Deng and Kangmu Ma and Xiaohuan Xia and Yunlong Huang and Zheng, {Jialin C.}",

note = "Funding Information: This work was supported in part by research grants from the National Basic Research Program of China (973 Program Grant No. 2014CB965001 to JZ), Innovative Research Groups of the National Natural Science Foundation of China (# 81221001 to JZ), and Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (# 81329002 to JZ), the National Institutes of Health : 1R01NS097195-01 (JZ). We thank Dr. Chao Lin (Tongji University, Shanghai, China) for the assistance with the DLS. We thank Dr. Bin Li (Shanghai Institute of Applied Physics, Chinese Academy of Science) for providing Nanosight NS300. We thank Lenal Bottoms and Justin Peer for proofreading the manuscript. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2019",

month = apr,

doi = "10.1016/j.nbd.2018.12.003",

language = "English",

volume = "124",

pages = "322--334",

}

TY - JOUR

T1 - Induced neural progenitor cells abundantly secrete extracellular vesicles and promote the proliferation of neural progenitors via extracellular signal–regulated kinase pathways

AU - Ma, Yizhao

AU - Wang, Kaizhe

AU - Pan, Jiabin

AU - Fan, Zhaohuan

AU - Tian, Changhai

AU - Deng, Xiaobei

AU - Ma, Kangmu

AU - Xia, Xiaohuan

AU - Huang, Yunlong

AU - Zheng, Jialin C.

N1 - Funding Information: This work was supported in part by research grants from the National Basic Research Program of China (973 Program Grant No. 2014CB965001 to JZ), Innovative Research Groups of the National Natural Science Foundation of China (# 81221001 to JZ), and Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (# 81329002 to JZ), the National Institutes of Health : 1R01NS097195-01 (JZ). We thank Dr. Chao Lin (Tongji University, Shanghai, China) for the assistance with the DLS. We thank Dr. Bin Li (Shanghai Institute of Applied Physics, Chinese Academy of Science) for providing Nanosight NS300. We thank Lenal Bottoms and Justin Peer for proofreading the manuscript. Publisher Copyright: © 2018 Elsevier Inc.

PY - 2019/4

Y1 - 2019/4

N2 - Neural stem/progenitor cells (NPCs) are known to have potent therapeutic effects in neurological disorders through the secretion of extracellular vesicles (EVs). Despite the therapeutic potentials, the numbers of NPCs are limited in the brain, curbing the further use of EVs in the disease treatment. To overcome the limitation of NPC numbers, we used a three transcription factor (Brn2, Sox2, and Foxg1) somatic reprogramming approach to generate induced NPCs (iNPCs) from mouse fibroblasts and astrocytes. The resulting iNPCs released significantly higher numbers of EVs compared with wild-type NPCs (WT-NPCs). Furthermore, iNPCs-derived EVs (iNPC-EVs) promoted NPC function by increasing the proliferative potentials of WT-NPCs. Characterizations of EV contents through proteomics analysis revealed that iNPC-EVs contained higher levels of growth factor-associated proteins that were predicted to activate the down-stream extracellular signal-regulated kinase (ERK) pathways. As expected, the proliferative effects of iNPC-derived EVs on WT-NPCs can be blocked by an ERK pathway inhibitor. Our data suggest potent therapeutic effects of iNPC-derived EVs through the promotion of NPC proliferation, release of growth factors, and activation of ERK pathways. These studies will help develop highly efficient cell-free therapeutic strategies for the treatment of neurological diseases.

AB - Neural stem/progenitor cells (NPCs) are known to have potent therapeutic effects in neurological disorders through the secretion of extracellular vesicles (EVs). Despite the therapeutic potentials, the numbers of NPCs are limited in the brain, curbing the further use of EVs in the disease treatment. To overcome the limitation of NPC numbers, we used a three transcription factor (Brn2, Sox2, and Foxg1) somatic reprogramming approach to generate induced NPCs (iNPCs) from mouse fibroblasts and astrocytes. The resulting iNPCs released significantly higher numbers of EVs compared with wild-type NPCs (WT-NPCs). Furthermore, iNPCs-derived EVs (iNPC-EVs) promoted NPC function by increasing the proliferative potentials of WT-NPCs. Characterizations of EV contents through proteomics analysis revealed that iNPC-EVs contained higher levels of growth factor-associated proteins that were predicted to activate the down-stream extracellular signal-regulated kinase (ERK) pathways. As expected, the proliferative effects of iNPC-derived EVs on WT-NPCs can be blocked by an ERK pathway inhibitor. Our data suggest potent therapeutic effects of iNPC-derived EVs through the promotion of NPC proliferation, release of growth factors, and activation of ERK pathways. These studies will help develop highly efficient cell-free therapeutic strategies for the treatment of neurological diseases.

KW - Cellular reprogramming

KW - ERK pathways

KW - Extracellular vesicles

KW - Growth factors

KW - Neural progenitor cells

KW - Proliferation

UR - http://www.scopus.com/inward/record.url?scp=85058207898&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058207898&partnerID=8YFLogxK

U2 - 10.1016/j.nbd.2018.12.003

DO - 10.1016/j.nbd.2018.12.003

M3 - Article

C2 - 30528256

AN - SCOPUS:85058207898

SN - 0969-9961

VL - 124

SP - 322

EP - 334

JO - Neurobiology of Disease

JF - Neurobiology of Disease

ER -

Induced neural progenitor cells abundantly secrete extracellular vesicles and promote the proliferation of neural progenitors via extracellular signal–regulated kinase pathways

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this