Chinese Researchers Break Through Bottlenecks in Diabetes Cell Therapy with Novel Strategy

The global number of diabetes patients has reached nearly 589 million, with about 148 million in China. Islet organoid transplantation derived from stem cells is widely recognized as a promising path for the functional cure of diabetes, yet its clinical translation has long been hindered by three major bottlenecks: insufficient functional maturity of transplanted cells, severe hypoxic stress injury after transplantation, and delayed vascularization of grafts.

Recently, a research team led by Professor Li Weida from Tongji University, in collaboration with a team from Yunnan Provincial First People’s Hospital, published their findings in the international academic journal Cell Stem Cell. According to People’s Daily, they proposed a new strategy to systematically address the above bottlenecks from the root—endowing stem cell-derived islet organoids with "stress-tolerant" characteristics by targeting and inhibiting the zinc transporter ZnT8, bringing a landmark progress to diabetes cell therapy.

The strategy stems from over a decade of systematic research by Professor Li Weida’s team on zinc metabolism and the pathogenesis of diabetes. In 2014, foreign scientists discovered that people with natural loss of ZnT8 protein function had an 80% lower risk of developing type 2 diabetes, but the specific mechanism remained unclear. Professor Li’s team successively revealed in journals such as Nature Communications that abnormal zinc accumulation mediated by ZnT8 is a key pathogenic factor for islet β-cell dysfunction, and developed the world’s first small-molecule inhibitor targeting ZnT8 based on this finding.

"We found that in islet organoids derived from stem cells, zinc levels in β-cells gradually increase during differentiation. Excessive zinc induces reactive oxygen species accumulation, leading to oxidative modification and inactivation of AMPK, a core regulatory protein for cellular energy metabolism, making cells unable to cope with the ischemic and hypoxic environment after transplantation," Professor Li Weida explained.

Using the self-screened small-molecule inhibitor SU6656, the team targeted and inhibited ZnT8, corrected abnormal zinc accumulation, and reactivated AMPK. The activated AMPK, like a "master switch", endows organoids with three characteristics: mature function with significantly enhanced insulin secretion, hypoxia tolerance to improve survival in ischemic environments, and promoted vascularization by upregulating vascular endothelial growth factor expression. This "three birds with one stone" strategy is named the novel "stress-tolerant islet organoid" technology.

This is not the first breakthrough of Professor Li’s team in diabetes cell therapy. In January this year, the team, together with Academician Gao Shaorong from the Chinese Academy of Sciences, published results in Cell Research, solving the problem of islet β-cell "identity loss" in a high-glucose environment, equivalent to stamping an "identity seal" on transplanted cells.

"These two studies have found the 'key' to improving the stability of cell therapy products from the source," commented Academician Gao Shaorong. "They form a 'combination punch' to develop clinically tested 'Made-in-China' cell drugs." Currently, Professor Li’s team is closely cooperating with Yunnan Provincial First People’s Hospital to advance clinical research. "We must embrace cutting-edge breakthroughs like stem cell therapy for major chronic diseases," said Hou Jianhong, President of Yunnan Provincial First People’s Hospital.