Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Feb 26, 2020; 12(2): 139-151
Published online Feb 26, 2020. doi: 10.4252/wjsc.v12.i2.139
Comparison between the therapeutic effects of differentiated and undifferentiated Wharton's jelly mesenchymal stem cells in rats with streptozotocin-induced diabetes
Chen-Yuan Hsiao, Tien-Hua Chen, Ben-Shian Huang, Po-Han Chen, Cheng-Hsi Su, Jia-Fwu Shyu, Pei-Jiun Tsai
Chen-Yuan Hsiao, Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
Chen-Yuan Hsiao, Department of Surgery, Landseed International Hospital, Taoyuan 324, Taiwan
Tien-Hua Chen, Po-Han Chen, Pei-Jiun Tsai, Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, Taipei 112, Taiwan
Tien-Hua Chen, Pei-Jiun Tsai, Trauma Center, Department of Surgery, Veterans General Hospital, Taipei 112, Taiwan
Tien-Hua Chen, Division of General Surgery, Department of Surgery, Veterans General Hospital, Taipei 112, Taiwan
Ben-Shian Huang, Department of Obstetrics and Gynecology, Veterans General Hospital, Taipei 112, Taiwan
Cheng-Hsi Su, Department of Surgery, Cheng Hsin General Hospital, Taipei 112, Taiwan
Jia-Fwu Shyu, Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan
Pei-Jiun Tsai, Department of Critical Care Medicine, Veterans General Hospital, Taipei 112, Taiwan
Author contributions: All authors participated in various aspects of the study and to the development of the report; Chen PH, Shyu JF, and Tsai PJ designed and performed all of the in vitro experiments; Hsiao CY, Chen TH, Huang BS, Su CH, and Tsai PJ designed and performed all of the animal experiments; Hsiao CY, Chen TH, Shyu JF, and Tsai PJ analyzed the statistical work and wrote the manuscript; Shyu JF and Tsai PJ contributed equally to this work; All authors reviewed and approved the manuscript.
Supported by Taipei Veterans General Hospital, No. V106B-024; Yen Tjing Ling Medical Foundation, No. CI-106-20; Cheng Hsin General Hospital, No. CY10716; Taiwan Ministry of Science and Technology, No. MOST 105-2314-B-010-010-MY3 and No. MOST 106-2314-B-010-009.
Institutional review board statement: The study was reviewed and approved by the Taipei Veterans General Hospital Institutional Review Board (2018-02-008BC).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Taipei Veterans General Hospital (IACUC protocol number: 2017-055).
Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript. All the Authors have no conflict of interest related to the manuscript.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at ( No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Pei-Jiun Tsai, MD, PhD, Assistant Professor, Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, 201 Shih-Pai Road Section 2, Taipei 112, Taiwan.
Received: August 27, 2019
Peer-review started: August 27, 2019
First decision: October 19, 2019
Revised: December 27, 2019
Accepted: January 6, 2020
Article in press: January 6, 2020
Published online: February 26, 2020
Research background

Despite the availability of current therapies, including oral antidiabetic drugs and insulin, to control the symptoms caused by high blood glucose, it is difficult to cure diabetes mellitus, especially type 1 diabetes mellitus.

Research motivation

Both islet transplantation and cadaveric whole pancreas transplantation are the treatment choice for diabetes. However, shortage of donors, high perioperative risks, and the long-term postoperative need of immunosuppressants are some of the major concerns and challenges for these treatments. More appropriate and effective medical technologies to cure diabetes are needed. Cell therapies using mesenchymal stem cells (MSCs) may be a promising option.

Research objectives

In this study, we tried to figure out the therapeutic mechanisms by which MSCs exert their effects for diabetic rats.

Research methods

We used three types of differentiation media over 10 d to generate insulin-producing cells (IPCs) from human Wharton’s jelly MSCs (hWJ-MSCs). We further transplanted the undifferentiated hWJ-MSCs and differentiated IPCs derived from them into the portal vein of rats with streptozotocin-induced diabetes and recorded the physiological and pathological changes.

Research results

Using fluorescent staining and C-peptide ELISA, we have shown that we were able to successfully induce the differentiation of hWJ-MSCs into IPCs. Transplantation of both IPCs derived from hWJ-MSCs and undifferentiated hWJ-MSCs had the therapeutic effect of ameliorating blood glucose levels and improving intraperitoneal glucose tolerance tests. The transplanted IPCs homed to the pancreas and functionally survived for at least 8 wk after transplantation, whereas the undifferentiated hWJ-MSCs were able to improve the insulitis and ameliorate the serum inflammatory cytokine in streptozotocin-induced diabetic rats.

Research conclusions

The therapeutic mechanism of differentiated and undifferentiated human hWJ-MSCs in streptozotocin-induced diabetic rats may be different. Differentiated IPCs can significantly improve blood glucose levels due to continuously secretion insulin by the transplanted cells that survived in the islets of diabetic rats. Transplantation of undifferentiated hWJ-MSCs can significantly improve insulitis and re-balance the inflammatory condition with only a slight improvement in blood glucose levels.

Research perspectives

The results of this study will provide basic and essential information for future application of cell regenerative therapy in diabetic patients.