Rapid and Efficient Direct Conversion of Human Adult Somatic Cells into Neural Stem Cells by HMGA2/let-7b

Kyung-Rok Yu; Ji-Hee Shin; Jae-Jun Kim; Myung Guen Koog; Jin Young Lee; Soon Won Choi; Hyung-Sik Kim; Yoojin Seo; SeungHee Lee; Tae-Hoon Shin; Min Ki Jee; Dong-Wook Kim; Sung Jun Jung; Sue Shin; Dong Wook Han; Kyung-Sun Kang

doi:10.1016/j.celrep.2014.12.038

Rapid and Efficient Direct Conversion of Human Adult Somatic Cells into Neural Stem Cells by HMGA2/let-7b

Cell Rep. 2015 Jan 20;10(3):441-452. doi: 10.1016/j.celrep.2014.12.038. Epub 2015 Jan 15.

Authors

Affiliations

¹ Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea; The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea.
² Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea; The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea; Institute for Stem Cell and Regenerative Medicine in Kang Stem Biotech, Biotechnology Incubating Center, Seoul National University, Seoul 151-742, Korea.
³ Department of Physiology and Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
⁴ Department of Physiology, School of Medicine, Hanyang University, Seoul 133-791, Korea.
⁵ Department of Laboratory Medicine, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, Seoul 156-707, Korea; Seoul Metropolitan Public Cord Blood Bank, Allcord, Seoul 156-707, Korea.
⁶ Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul 143-701, Korea.
⁷ Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea; The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea. Electronic address: kangpub@snu.ac.kr.

PMID: 25600877
DOI: 10.1016/j.celrep.2014.12.038

Abstract

A recent study has suggested that fibroblasts can be converted into mouse-induced neural stem cells (miNSCs) through the expression of defined factors. However, successful generation of human iNSCs (hiNSCs) has proven challenging to achieve. Here, using microRNA (miRNA) expression profile analyses, we showed that let-7 microRNA has critical roles for the formation of PAX6/NESTIN-positive colonies from human adult fibroblasts and the proliferation and self-renewal of hiNSCs. HMGA2, a let-7-targeting gene, enables induction of hiNSCs that displayed morphological/molecular features and in vitro/in vivo differentiation potential similar to H9-derived NSCs. Interestingly, HMGA2 facilitated the efficient conversion of senescent somatic cells or blood CD34+ cells into hiNSCs through an interaction with SOX2, whereas other combinations or SOX2 alone showed a limited conversion ability. Taken together, these findings suggest that HMGA2/let-7 facilitates direct reprogramming toward hiNSCs in minimal conditions and maintains hiNSC self-renewal, providing a strategy for the clinical treatment of neurological diseases.