Direct and selective lineage conversion of human fibroblasts to dopaminergic precursors

Miao He, Hainan Zhang, Yuju Li, Changhai Tian, Beisha Tang, Yunlong Huang, Jialin Zheng

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Transplantation of dopaminergic precursors (DPs) is a promising therapeutic strategy of Parkinson's disease (PD). However, limited cell source for dopaminergic precursors has become a major obstacle for transplantation therapy. Our group demonstrated previously that mouse fibroblasts can be reprogrammed into induced dopaminergic precursors (iDPs) with high differentiation efficiency. In the current study, we hypothesized that a similar strategy can be applied to generate human iDPs for future cell therapy of PD. We overexpressed transcription factors Brn2, Sox2, and Foxa2 in human fibroblasts and observed formation of neurospheres. Subsequent characterization of the precursor colonies confirmed the generation of human induced dopaminergic precursors (hiDPs). These hiDPs were capable of self-renewal, proliferation, and differentiation. The hiDPs demonstrated high immunoreactivity for neural progenitor markers and high levels of gene expression for ventral mesencephalon-related neural progenitor markers such as Lmx1a, NIKX6.1, Corin, Otx2 and Mash1. Furthermore, the hiDPs could be differentiated into dopaminergic neurons with ˜80% efficiency, which significantly increased major functionally relevant proteins such as TH, DAT, AADC, Lmx1B, and VMAT2 compared to hiDPs. Additionally, hiDPs are more dopaminergic progenitor-restricted compare to those hiDP-like cells reprogrammed only by Brn2 and Sox2. Together, these results suggest that hiDPs with high differentiation efficiency can be generated by direct lineage reprogramming of fibroblasts with transcription factors Brn2, Sox2, and Foxa2. These hiDPs may serve as a safe and effective cell source for transplantation treatment of PD.

Original languageEnglish
Pages (from-to)16-23
Number of pages8
JournalNeuroscience Letters
Volume699
DOIs
StatePublished - Apr 23 2019

Bibliographical note

Funding Information:
This work was supported by grants from National Key Basic Research Program of China (973Program Grant No. 2014CB965000 , project 1 No. 2014CB965001, JZ), National Key Plan for Scientific Research and development of China ( 2016YFC1306000 , BT), National Natural Science Foundation of China ( 81430023 , BT), State Key Program of the National Natural Science Foundation of China (#81830037 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); National Institutes of Health : 1R01NS097195-01 (JZ), and 2P30MH062261 , Developmental (YH).

Publisher Copyright:
© 2019 Elsevier B.V.

Keywords

  • Cell reprogramming
  • Dopaminergic precursor
  • Parkinson's disease

ASJC Scopus subject areas

  • Neuroscience (all)

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