Shkreli, M. | Search bioRxiv

bioRxiv2025

Inhibition of eIF5A hypusination improves pancreatic islet transplantation outcomes by promoting ischemia tolerance

Pancreatic islet transplantation provides substantial benefits for individuals with Type 1 Diabetes (T1D). However, the low yield of the procedure limits its therapeutic potential, as multiple injections from different donors are needed to provide sufficient islets for a single recipient. Many islets are lost during preparation and transplantation, primarily due to ischemia/reperfusion injuries. GC7 (N1-guanyl-1,7-diaminoheptane), an inhibitor of eIF5A hypusination, improves the resistance of various cells to ischemia/reperfusion. Our study therefore explored whether ex-situ conditioning of pancreatic islets with GC7 during the preparation process could serve as a strategy to enhance the outcomes of pancreatic islet transplantation. Conditioning of mouse primary islets with GC7 at the digestion step of the pancreas significantly improved the procedure yield. Indeed, islets showed better survival at 24h and 72h after isolation and major protection against ischemia/reperfusion injury. Finally, the transplantation of a suboptimal number of islets under the renal capsule of hyperglycemic mice demonstrated superior functionality and survival of islets conditioned with GC7 compared to control islets. Collectively, these findings demonstrate that conditioning pancreatic islets with GC7 enhances their resistance to ischemia-reperfusion injury and significantly improves the efficiency of pancreatic islet transplantation. Hence the use of GC7 appears as a promising strategy to win one of the major challenges currently faced in the field of Type 1 diabetes.

cell biology↗

bioRxiv2021

A ganglioside-based senescence-associated immune checkpoint

Senescent cells accumulate in aging tissues, and their elimination can favor healthy aging1-4. Therefore, therapeutic interventions targeting cellular senescence may be promising strategies for delaying or reversing a vast range of age-related diseases5. As cells of the immune system are responsible for senescent cell elimination6-11, a possible anti-aging and pro-healthspan treatment is the specific activation of the immune system to induce senescent cell clearance. However, whether this elimination is limited by an immune checkpoint leading to tolerance of senescence cells is currently unknown. Here, we show that cellular senescence, elicited by various stressors other than oncogenic activation, triggers immune escape toward natural killer (NK) cells, which may thus limit the use of anti-senescence immunotherapies. Moreover, using mass spectrometry, we reveal that senescent cells reshuffle their glycosphingosine composition, toward a marked increase in the ganglioside content, including the appearance of disialylated ganglioside GD3. This senescence associated GD3 overexpression results from transcriptional upregulation of the gene encoding the enzyme ST8SIA1, which is responsible for GD3 synthesis. The high level of GD3 leads to a strong immunosuppressive signal affecting NK cell-mediated immunosurveillance. In a mouse model of lung fibrosis, senescent cell-dependent NK cell immunosuppression is blunted by in vivo administration of anti-GD3 monoclonal antibodies leading to a clear anti-fibrotic effect. These results demonstrate that GD3 upregulation in senescent cells drives a switch from immune clearance toward immune tolerance of senescent cells. Therefore, we propose that GD3 level acts as a senescence-associated immune checkpoint (SIC) that regulates NK cell functions toward senescent cells. Thus, targeting GD3 with specific antibodies may be a promising strategy for the development of effective anti-senescence immunotherapies.

immunology↗