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World J Stem Cells. Mar 26, 2021; 13(3): 193-207
Published online Mar 26, 2021. doi: 10.4252/wjsc.v13.i3.193
Functional maturation of immature β cells: A roadblock for stem cell therapy for type 1 diabetes
Zi-Yi Sun, Ting-Yan Yu, Fang-Xu Jiang, Wei Wang
Zi-Yi Sun, Ting-Yan Yu, Fang-Xu Jiang, Wei Wang, Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
Fang-Xu Jiang, School of Biomedical Science, University of Western Australia, Nedlands 6009, Australia
Fang-Xu Jiang, School of Health and Medical Sciences, Edith Cowan University, Perth 6000, Australia
Author contributions: Sun ZY wrote the paper; Yu TY drew the figures; Jiang FX and Wang W proposed the ideas, revised the manuscript, and finally approved the submission.
Supported by the National Natural Science Foundation of China, No. 81471081; the Natural Science Foundation of Fujian Province, China, No. 2019J01010; Xiamen Research Foundation for Science and Technology Project No. 3502Z20194037; and Scientific Research Foundation for Advanced Talents, Xiang’an Hospital of Xiamen University, No. PM201809170005.
Conflict-of-interest statement: The authors declare no conflict of interests for this article.
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: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wei Wang, MD, Doctor, Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, No. 2000 Xiang'an East Road, Xiang'an District, Xiamen 361100, Fujian Province, China. wwei19742007@hotmail.com
Received: August 29, 2020
Peer-review started: August 29, 2020
First decision: January 7, 2021
Revised: January 19, 2021
Accepted: February 25, 2021
Article in press: February 25, 2021
Published online: March 26, 2021
Abstract

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by the specific destruction of pancreatic islet β cells and is characterized as the absolute insufficiency of insulin secretion. Current insulin replacement therapy supplies insulin in a non-physiological way and is associated with devastating complications. Experimental islet transplantation therapy has been proven to restore glucose homeostasis in people with severe T1DM. However, it is restricted by many factors such as severe shortage of donor sources, progressive loss of donor cells, high cost, etc. As pluripotent stem cells have the potential to give rise to all cells including islet β cells in the body, stem cell therapy for diabetes has attracted great attention in the academic community and the general public. Transplantation of islet β-like cells differentiated from human pluripotent stem cells (hPSCs) has the potential to be an excellent alternative to islet transplantation. In stem cell therapy, obtaining β cells with complete insulin secretion in vitro is crucial. However, after much research, it has been found that the β-like cells obtained by in vitro differentiation still have many defects, including lack of adult-type glucose stimulated insulin secretion, and multi-hormonal secretion, suggesting that in vitro culture does not allows for obtaining fully mature β-like cells for transplantation. A large number of studies have found that many transcription factors play important roles in the process of transforming immature to mature human islet β cells. Furthermore, PDX1, NKX6.1, SOX9, NGN3, PAX4, etc., are important in inducing hPSC differentiation in vitro. The absent or deficient expression of any of these key factors may lead to the islet development defect in vivo and the failure of stem cells to differentiate into genuine functional β-like cells in vitro. This article reviews β cell maturation in vivo and in vitro and the vital roles of key molecules in this process, in order to explore the current problems in stem cell therapy for diabetes.

Keywords: Stem cell therapy, Type 1 diabetes mellitus, β cell, Maturation

Core Tip: Type 1 diabetes is a metabolic disease characterized by absolute lack of insulin. Current insulin replacement therapy supplies insulin in a non-physiological way and is associated with devastating complications. Diabetes stem cell therapy with insulin-producing β-like cells differentiated in vitro from human pluripotent stem cells has recently attracted great interest in the academic community and the general public. Although great progress has been made, the β-like cells differentiated in vitro still have many defects. Here we summarize the latest knowledge on β-cell maturation in vivo and in vitro and the vital roles of key molecules in this process, in order to explore the current problems in diabetes stem cell therapy.