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

13 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

Fingerprint

Fibroblasts
Neurons
Brain
Extracellular Matrix
Therapeutics
Animals
Hydrogels
Locomotives
Substrates
Cues
Transfection
Plasmids
Animal Models
Stroke
Tissue
Efficiency
Recovery

All Science Journal Classification (ASJC) codes

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

Cite this

Jin, Yoonhee ; Lee, Jung Seung ; Kim, Jin ; Min, Sungjin ; Wi, Soohyun ; Yu, Ji Hea ; Chang, Gyeong Eon ; Cho, Ann Na ; Choi, Yeeun ; Ahn, Da Hee ; Cho, Sung Rae ; Cheong, Eunji ; Kim, Yun Gon ; Kim, Hyong Pyo ; Kim, Yonghwan ; Kim, Dong Seok ; Kim, Hyun Woo ; Quan, Zhejiu ; Kang, Hoon Chul ; Cho, Seung Woo. / Three-dimensional brain-like microenvironments facilitate the direct reprogramming of fibroblasts into therapeutic neurons. In: Nature biomedical engineering. 2018 ; Vol. 2, No. 7. pp. 522-539.
@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}",
year = "2018",
month = "7",
day = "1",
doi = "10.1038/s41551-018-0260-8",
language = "English",
volume = "2",
pages = "522--539",
journal = "Nature Biomedical Engineering",
issn = "2157-846X",
publisher = "Nature Publishing Group",
number = "7",

}

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

Three-dimensional brain-like microenvironments facilitate the direct reprogramming of fibroblasts into therapeutic neurons. / Jin, Yoonhee; Lee, Jung Seung; Kim, Jin; Min, Sungjin; Wi, Soohyun; Yu, Ji Hea; Chang, Gyeong Eon; Cho, Ann Na; Choi, Yeeun; Ahn, Da Hee; Cho, Sung Rae; Cheong, Eunji; Kim, Yun Gon; Kim, Hyong Pyo; Kim, Yonghwan; Kim, Dong Seok; Kim, Hyun Woo; Quan, Zhejiu; Kang, Hoon Chul; Cho, Seung Woo.

In: Nature biomedical engineering, Vol. 2, No. 7, 01.07.2018, p. 522-539.

Research output: Contribution to journalArticle

TY - JOUR

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

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85049861321&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049861321&partnerID=8YFLogxK

U2 - 10.1038/s41551-018-0260-8

DO - 10.1038/s41551-018-0260-8

M3 - Article

C2 - 30948831

AN - SCOPUS:85049861321

VL - 2

SP - 522

EP - 539

JO - Nature Biomedical Engineering

JF - Nature Biomedical Engineering

SN - 2157-846X

IS - 7

ER -