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

doi:10.1038/s41551-018-0260-8

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 journal › Article › peer-review

72 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 language	English
Pages (from-to)	522-539
Number of pages	18
Journal	Nature biomedical engineering
Volume	2
Issue number	7
DOIs	https://doi.org/10.1038/s41551-018-0260-8
Publication status	Published - 2018 Jul 1

Bibliographical note

Funding Information:
This work was supported by grants (2018M3A9H1021382, 2017R1A2B3005994 and 2014R1A2A11052042) from the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT (MSIT), Republic of Korea. This work was supported by the Institute for Basic Science (IBS-R026-D1). It was also supported in part by a grant (HI14C1588) from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health and Welfare, Republic of Korea.

Publisher Copyright:
© 2018 The Author(s).

All Science Journal Classification (ASJC) codes

Biotechnology
Bioengineering
Medicine (miscellaneous)
Biomedical Engineering
Computer Science Applications

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10.1038/s41551-018-0260-8

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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

@article{22cc2fdd78274cd09ed977f64d887e79,

title = "Three-dimensional brain-like microenvironments facilitate the direct reprogramming of fibroblasts into therapeutic neurons",

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.",

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

note = "Funding Information: This work was supported by grants (2018M3A9H1021382, 2017R1A2B3005994 and 2014R1A2A11052042) from the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT (MSIT), Republic of Korea. This work was supported by the Institute for Basic Science (IBS-R026-D1). It was also supported in part by a grant (HI14C1588) from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health and Welfare, Republic of Korea. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = jul,

day = "1",

doi = "10.1038/s41551-018-0260-8",

language = "English",

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Jin, Y, Lee, JS, Kim, J, Min, S, Wi, S, Yu, JH, Chang, GE, Cho, AN, Choi, Y, Ahn, DH, Cho, SR , Cheong, E, Kim, YG, Kim, HP, Kim, Y, Kim, DS, Kim, HW, Quan, Z, Kang, HC & Cho, SW 2018, 'Three-dimensional brain-like microenvironments facilitate the direct reprogramming of fibroblasts into therapeutic neurons', Nature biomedical engineering, vol. 2, no. 7, pp. 522-539. https://doi.org/10.1038/s41551-018-0260-8

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T1 - Three-dimensional brain-like microenvironments facilitate the direct reprogramming of fibroblasts into therapeutic neurons

AU - Jin, Yoonhee

AU - Lee, Jung Seung

AU - Kim, Jin

AU - Min, Sungjin

AU - Wi, Soohyun

AU - Yu, Ji Hea

AU - Chang, Gyeong Eon

AU - Cho, Ann Na

AU - Choi, Yeeun

AU - Ahn, Da Hee

AU - Cho, Sung Rae

AU - Cheong, Eunji

AU - Kim, Yun Gon

AU - Kim, Hyong Pyo

AU - Kim, Yonghwan

AU - Kim, Dong Seok

AU - Kim, Hyun Woo

AU - Quan, Zhejiu

AU - Kang, Hoon Chul

AU - Cho, Seung Woo

N1 - Funding Information: This work was supported by grants (2018M3A9H1021382, 2017R1A2B3005994 and 2014R1A2A11052042) from the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT (MSIT), Republic of Korea. This work was supported by the Institute for Basic Science (IBS-R026-D1). It was also supported in part by a grant (HI14C1588) from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health and Welfare, Republic of Korea. Publisher Copyright: © 2018 The Author(s).

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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.

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

Abstract

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