Synergistic effects of carboxymethyl-hexanoyl chitosan, cationic polyurethane-short branch PEI in miR122 gene delivery: Accelerated differentiation of iPSCs into mature hepatocyte-like cells and improved stem cell therapy in a hepatic failure model

被引：37

作者：

Chien, Yueh ^{[1
,9
]}

Chang, Yuh-Lih ^{[1
,9
]}

Li, Hsin-Yang ^{[2
,5
]}

Larsson, Mikael ^{[3
]}

Wu, Wai-Wah ^{[2
,4
]}

Chien, Chian-Shiu ^{[1
,9
]}

Wang, Chien-Ying ^{[2
,6
]}

Chu, Pen-Yuan ^{[2
,7
]}

Chen, Kuan-Hsuan ^{[2
,10
]}

Lo, Wen-Liang ^{[2
,11
]}

Chiou, Shih-Hwa ^{[1
,2
,9
]}

Lan, Yuan-Tzu ^{[2
,6
]}

Huo, Teh-Ia ^{[1
,8
]}

Lee, Shou-Dong ^{[4
]}

Huang, Pin-I ^{[1
,2
,12
]}

机构：

[1] Natl Yang Ming Univ, Inst Pharmacol, Taipei 112, Taiwan

[2] Natl Yang Ming Univ, Inst Clin Med, Taipei 112, Taiwan

[3] Univ S Australia, Ian Wark Res Inst, Mawson Lakes, SA 5095, Australia

[4] Cheng Hsin Gen Hosp, Dept Med, Div Gastroenterol, Taipei, Taiwan

[5] Taipei Vet Gen Hosp, Dept Obstet & Gynecol, Taipei, Taiwan

[6] Taipei Vet Gen Hosp, Dept Surg, Taipei, Taiwan

[7] Taipei Vet Gen Hosp, Dept Otolaryngol, Taipei, Taiwan

[8] Taipei Vet Gen Hosp, Dept Internal Med, Div Gastroenterol, Taipei, Taiwan

[9] Taipei Vet Gen Hosp, Dept Med Res & Educ, Taipei, Taiwan

[10] Taipei Vet Gen Hosp, Dept Pharm, Taipei, Taiwan

[11] Taipei Vet Gen Hosp, Dept Stomatol, Div Oral & Maxillofacial Surg, Taipei, Taiwan

[12] Taipei Vet Gen Hosp, Dept Oncol, Div Radiat Oncol, Taipei, Taiwan

来源：

ACTA BIOMATERIALIA | 2015年 / 13卷

关键词：

Induced pluripotent stem cells; miR122; Acute hepatic failure; Nano structured chitosan; IN-VITRO; CIRCULATING MICRORNA-122; NANOPARTICLES; GENERATION; OVEREXPRESSION; INHIBITION; INDUCTION; HYDROGEL;

D O I：

10.1016/j.actbio.2014.11.018

中图分类号：

R318 [生物医学工程];

学科分类号：

100103 [病原生物学];

摘要：

MicroRNA122 (miR122), a liver-specific microRNA, plays critical roles in homeostatic regulation and hepatic-specific differentiation. Induced pluripotent stem cells (iPSCs) have promising potential in regenerative medicine, but it remains unknown whether non-viral vector-mediated miR122 delivery can enhance the differentiation of iPSCs into hepatocyte-like cells (iPSC-Heps) and rescue thioacetamide-induced acute hepatic failure (AHF) in vivo. In this study, we demonstrated that embedment of miR122 complexed with polyurethane-graft-short-branch polyethylenimine copolymer (PU-PEI) in nanostructured amphiphatic carboxymethyl-hexanoyl chitosan (CHC) led to dramatically enhanced miR122 delivery into human dental pulp-derived iPSCs (DP-iPSCs) and facilitated these DP-iPSCs to differentiate into iPSC-Heps (miR122-iPSC-Heps) with mature hepatocyte functions. Microarray and bioinformatics analysis further indicated that CHC/PU-PEI-miR122 promoted the gene-signature pattern of DP-iPSCs to shift into a liver-specific pattern. Furthermore, intrahepatic delivery of miR122-iPSC-Heps, but not miR-Scr-iPSC-Heps, improved liver functions and rescued recipient survival, and CHC-mediated delivery showed a better efficacy than that using phosphate buffered saline as a delivery vehicle. In addition, these transplanted miR122-iPSC-Heps remained viable and could produce circulatory albumin for 4 months. Taken together, our findings demonstrate that non-viral delivery of miR122 shortens the time of iPSC differentiation into hepatocytes and the delivery of miR122-iPSC-Heps using CHC as a vehicle exhibited promising hepatoprotective efficacy in vivo. miR122-iPSC-Heps may represent a feasible cell source and provide an efficient and alternative strategy for hepatic regeneration in AHF. (C) 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

引用

页码：228 / 244

页数：17

共 33 条

[1]

Ultrasensitive Multiplexed MicroRNA Quantification on Encoded Gel Microparticles Using Rolling Circle Amplification [J].