image: α/β/δ GFP-labeled mice of different ages were treated with HFD or STZ in order to create the diabetic mouse model. There is no reciprocal identity change of mouse islet cells after HFD treatment while β-cells undergo complex identity changes through the recovery after STZ treatment.
Credit: ©Science China Press
This study is led by professor Tao Yang (Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University). The team generated islet cell type-specific (Gcg/α-, Ins/β-, and Sst/δ) green fluorescent protein (GFP)-labeled mice for genetic lineage tracing using Cre-LoxP systems, thereinto β-cell GFP-labeled mice were tamoxifen (TAM) induced. The team utilized HFD or STZ to induce various diabetes models initiated at aged 7wk (youth-initiated HFD) or 12wk (adulthood-initiated HFD) and observed for12 weeks.
After 12wk HFD or control diet, mice pancreases of each group were extracted for further analysis. Frozen sections obtained from the pancreases were used to visualized the co-localization of GFP and INS/GCG/GFP through Immunofluorescence. After analyzing the immunofluorescence staining results, it was found that β-cells expand by self-replication and rarely trans-differentiate into α or δ cells in HFD-fed diabetic mice with distinct age of initiation.
When focusing on the STZ-induced diabetic mice, quite different results were observed. After 6wk or 12wk of STZ treatment, the team found that GFP and INS co-staining indicated a striking loss of INS+ among GFP+ cells from STZ treated mice compared to the control mice. Interestingly, the percentage of INS+ among GFP+ cells increased over time indicating the regain of β-cell identity after remarkable dedifferentiation.
To determine the source of the recovered β cells, the team calculated the percentage of GFP+ among INS+ cells and found that the recovered β cells arose from pre-existing β-cells. Unexpectedly, the evidence of trans-differentiation of α-cells into β-cells were found in STZ treated Gcg/α-lineage-labeled mice. The phenomenon of δ-cells trans-differentiating into β-cells was also foune in Sst/δ-lineage-labeled mice.
The contradictory results caught the attention of the team members. To explore the reasons for this paradoxical results, co-staining of GCG, SST, and GFP in Ins/β-lineage-labeled STZ-treated mice was analyzed. The percentage of α-cells or δ-cells (transdifferentiated from pre-existing β-cells) decreased from 6wk to 12wk after STZ treatment, which indicated that β cells could trans-differentiate to α and δ cells, meanwhile, α and δ cells trans-differentiate from β cells might re-trans-differentiate into β cells after recovery. Collectively, although the re-dedifferentiation of β-cells is the pivotal manner of β-cell recovery, α and δ cells that trans-differentiate from β cells might also re-trans-differentiate into β cells, thereby benefiting islet β cell regeneration after STZ-induced injury.
To further understand the characteristics of de- and trans-differentiation of islet cells, the team performed scRNA-seq of mouse islets in STZ-induced diabetes. ScRNA-seq confirmed the dynamic changes of β cell differentiation and mature status in mice with STZ-induced diabetes. Pathways such as mitochondrial function activation and chromatin modification and remodeling may play pivotal roles in the transition of pancreatic islet β cells.
In summary, this study demonstrates that β cells undergone completely different adaptation processes under various diabetic models and shed light on how islet β cells overcome the injuries in T1D and T2D pathogenesis.
http://engine.scichina.com/doi/10.1007/s11427-022-2372-y
Journal
Science China Life Sciences