Three-dimensional brain-like microenvironments facilitate the direct reprogramming of fibroblasts into therapeutic neurons

Yoonhee Jin, Jung Seung Lee, Jin Kim, Sungjin Min, Soohyun Wi, Ji Hea Yu, Gyeong Eon Chang, Ann Na Cho, Yeeun Choi, Da Hee Ahn, Sung Rae Cho, Eunji Cheong, Yun Gon Kim, Hyong Pyo Kim, Yonghwan Kim, Dong Seok Kim, Hyun Woo Kim, Zhejiu Quan, Hoon Chul Kang, Seung Woo Cho

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Biophysical cues can improve the direct reprogramming of fibroblasts into neurons that can be used for therapeutic purposes. However, the effects of a three-dimensional (3D) environment on direct neuronal reprogramming remain unexplored. Here, we show that brain extracellular matrix (BEM) decellularized from human brain tissue facilitates the plasmid-transfection-based direct conversion of primary mouse embryonic fibroblasts into induced neuronal (iN) cells. We first show that two-dimensional (2D) surfaces modified with BEM significantly increase the generation efficiency of iN cells and enhance neuronal transdifferentiation and maturation. Moreover, in an animal model of ischaemic stroke, iN cells generated on the BEM substrates and transplanted into the brain led to significant improvements in locomotive behaviours. We also show that compared with the 2D BEM substrates, 3D BEM hydrogels recapitulating brain-like microenvironments further promote neuronal conversion and potentiate the functional recovery of the animals. Our findings suggest that 3D microenvironments can boost nonviral direct reprogramming for the generation of therapeutic neuronal cells.

Original languageEnglish
Pages (from-to)522-539
Number of pages18
JournalNature biomedical engineering
Volume2
Issue number7
DOIs
Publication statusPublished - 2018 Jul 1

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Bioengineering
  • Medicine (miscellaneous)
  • Biomedical Engineering
  • Computer Science Applications

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    Jin, Y., Lee, J. S., Kim, J., Min, S., Wi, S., Yu, J. H., Chang, G. E., Cho, A. N., Choi, Y., Ahn, D. H., Cho, S. R., Cheong, E., Kim, Y. G., Kim, H. P., Kim, Y., Kim, D. S., Kim, H. W., Quan, Z., Kang, H. C., & Cho, S. W. (2018). Three-dimensional brain-like microenvironments facilitate the direct reprogramming of fibroblasts into therapeutic neurons. Nature biomedical engineering, 2(7), 522-539. https://doi.org/10.1038/s41551-018-0260-8