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Improvement of the therapeutic capacity of insulin-producing cells trans-differentiated from human liver cells using engineered cell sheet

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Abstract
Background: Although pancreatic islet transplantation therapy is ideal for diabetes patients, several hurdles have
prevented it from becoming a standard treatment, including donor shortage and low engraftment efficacy. In this
study, we prepared insulin-producing cells trans-differentiated from adult human liver cells as a new islet source.
Also, cell sheet formation could improve differentiation efficiency and graft survival.
Methods: Liver cells were expanded in vitro and trans-differentiated to IPCs using adenovirus vectors carrying
human genes for PDX1, NEUROD1, and MAFA. IPCs were seeded on temperature-responsive culture dishes to form
cell sheets. Differentiation efficiency was confirmed by ß cell-specific gene expression, insulin production, and
immunohistochemistry. IPC suspension was injected by portal vein (PV), and IPC sheet was transplanted on the liver
surface of the diabetic nude mouse. The therapeutic effect of IPC sheet was evaluated by comparing blood glucose
control, weight gain, histological evaluation, and hepatotoxicity with IPC injection group. Also, cell biodistribution
was assessed by in vivo/ex vivo fluorescence image tagging.
Results: Insulin gene expression and protein production were significantly increased on IPC sheets compared with
those in IPCs cultured on conventional culture dishes. Transplanted IPC sheets displayed significantly higher
engraftment efficiency and fewer transplanted cells in other organs than injected IPCs, and also lower liver toxicity,
improved blood glucose levels, and weight gain. Immunohistochemical analyses of liver tissue revealed positive
staining for PDX1 and insulin at 1, 2, and 4 weeks after IPC transplantation.
Conclusions: In conclusion, cell sheet formation enhanced the differentiation function and maturation of IPCs
in vitro. Additionally, parameters for clinical application such as distribution, therapeutic efficacy, and toxicity were
favorable. The cell sheet technique may be used with IPCs derived from various cell sources in clinical applications.
Keywords: Liver cell, Insulin-producing cell, Diabetics, Cell sheet, Transplantation
Issued Date
2021
Type
Article
Keyword
cell sheetdiabeticsinsulinproducing cellliver celltransplantation
DOI
10.1186/s13287-020-02080-0
URI
http://oak.ulsan.ac.kr/handle/2021.oak/8005
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_doaj_primary_oai_doaj_org_article_08564bbe2b5f48bca64eda67269e6dc2&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Improvement%20of%20the%20therapeutic%20capacity%20of%20insulin-producing%20cells%20trans-differentiated%20from%20human%20liver%20cells%20using%20engineered%20cell%20sheet&offset=0&pcAvailability=true
Publisher
Stem Cell Research & Therapy
Location
영국
Language
영어
ISSN
1757-6512
Citation Volume
12
Citation Number
1
Citation Start Page
3
Citation End Page
0
Appears in Collections:
Medicine > Medicine
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