Theranostics 2020; 10(6):2817-2831. doi:10.7150/thno.38553

Research Paper

FGF9 induces functional differentiation to Schwann cells from human adipose derived stem cells

Chia-Wei Huang1,7*, Shih-Yu Lu2*, Tzu-Chieh Huang1,7, Bu-Miim Huang2, H. Sunny Sun3, Shang-Hsun Yang4, Jih-Ing Chuang4, Yuan-Yu Hsueh5,6,7, Yi-Ting Wu2,8, Chia-Ching Wu1,2,6,7✉

1. Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan
2. Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan 701, Taiwan
3. Institute of molecular medicine, National Cheng Kung University, Tainan 701, Taiwan
4. Department of Physiology, National Cheng Kung University, Tainan 701, Taiwan
5. Division of Plastic Surgery, National Cheng Kung University Hospital, Tainan 704, Taiwan
6. Institute of Clinical Medicine, National Cheng Kung University, Tainan 701, Taiwan
7. International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan 701, Taiwan
8. Department of Nursing, Tzu Hui Institute of Technology, Pingtung 926, Taiwan
*Co-first authors

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Citation:
Huang CW, Lu SY, Huang TC, Huang BM, Sun HS, Yang SH, Chuang JI, Hsueh YY, Wu YT, Wu CC. FGF9 induces functional differentiation to Schwann cells from human adipose derived stem cells. Theranostics 2020; 10(6):2817-2831. doi:10.7150/thno.38553. Available from http://www.thno.org/v10p2817.htm

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Abstract

Rationale: The formation of adipose-derived stem cells (ASCs) into spheres on a chitosan-coated microenvironment promoted ASCs differentiation into a mixed population of neural lineage-like cells (NLCs), but the underline mechanism is still unknown. Since the fibroblast growth factor 9 (FGF9) and fibroblast growth factor receptors (FGFRs) play as key regulators of neural cell fate during embryo development and stem cell differentiation, the current study aims to reveal the interplay of FGF9 and FGFRs for promoting peripheral nerve regeneration.

Methods: Different concentration of FGF9 peptide (10, 25, 50, 100 ng/mL) were added during NLCs induction (FGF9-NLCs). The FGFR expressions and potential signaling were studied by gene and protein expressions as well as knocking down by specific FGFR siRNA or commercial inhibitors. FGF9-NLCs were fluorescent labeled and applied into a nerve conduit upon the injured sciatic nerves of experimental rats.

Results: The FGFR2 and FGFR4 were significantly increased during NLCs induction. The FGF9 treated FGF9-NLCs spheres became smaller and changed into Schwann cells (SCs) which expressed S100β and GFAP. The specific silencing of FGFR2 diminished FGF9-induced Akt phosphorylation and inhibited the differentiation of SCs. Transplanted FGF9-NLCs participated in myelin sheath formation, enhanced axonal regrowth and promoted innervated muscle regeneration. The knockdown of FGFR2 in FGF9-NLCs led to the abolishment of nerve regeneration.

Conclusions: Our data therefore demonstrate the importance of FGF9 in the determination of SC fate via the FGF9-FGFR2-Akt pathway and reveal the therapeutic benefit of FGF9-NLCs.

Keywords: FGF9, FGFR2, adipose-derived stem cell, neurosphere, Schwann cell differentiation