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

Research output: Contribution to journalArticlepeer-review

26 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 languageEnglish
Pages (from-to)322-334
Number of pages13
JournalNeurobiology of Disease
Volume124
DOIs
StatePublished - 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

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