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.

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Abstract

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.

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Journal ID (iso-abbrev): Acta Biomater

Title: Acta biomaterialia

ISSN (Electronic): 1878-7568

ISSN (Print): 1742-7061

Publication date (Electronic): Feb 2015

Volume: 13

Affiliations

[1 ] Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.

[2 ] Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan.

[3 ] Ian Wark Research Institute, University of South Australia, Mawson Lakes Campus, Mawson Lakes, SA 5095, Australia.

[4 ] Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan.

[5 ] Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.

[6 ] Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Laryngology and Head and Neck Surgery, Department of Otolaryngology, Taipei Veterans General Hospital, Taipei, Taiwan.

[7 ] Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan.

[8 ] Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Oral and Maxillofacial Surgery, Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan.

[9 ] Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.

[10 ] Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: ytlan@vghtpe.gov.tw.

[11 ] Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan; Division of Gastroenterology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

[12 ] Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan.

[13 ] Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Radiation Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: pihuang@vghtpe.gov.tw.

Article

Publisher Item ID: S1742-7061(14)00512-1

DOI: 10.1016/j.actbio.2014.11.018

PubMed ID: 25463491

SO-VID: 2b5f938e-6654-40a2-8ba2-59de6ae3f30e

History

Keywords: Acute hepatic failure,Induced pluripotent stem cells,Nano structured chitosan,miR122

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Keywords: Acute hepatic failure, Induced pluripotent stem cells, Nano structured chitosan, miR122

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.

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