Exploring senescence as a modifier of β cell extracellular vesicles in type 1 diabetes

Abstract

Type 1 Diabetes (T1D) is a chronic metabolic disease resulting from insulin deficiency due to autoimmune loss of pancreatic β cells. In addition to β cell destruction, it is now accepted that β cell stress and dysfunction, such as senescence, plays a crucial role in the development of the disease. Accumulation of senescent β cells occurs during development of T1D in humans and contributes to the progression of T1D in the nonobese diabetic (NOD) mouse model. Senescent β cells are thought to exacerbate the inflammatory response within the islets by production and secretion of senescence-associated secretory phenotype (SASP). Extracellular vesicles (EVs) from β cells have been shown to carry protein and microRNAs (miRNAs), influencing cellular signaling and may contribute to the development of T1D but it remains to be addressed how senescence impacts β cell EV cargo. In this minireview, we discuss emerging evidence that EV cargo proteins and miRNAs associated with senescence could contribute to the development of T1D and could suggest potential biomarkers and therapeutic targets for the regulation of SASP and elimination of senescent β cells in T1D. Future investigation exploring the intricate relationship between β cell senescence, EVs and miRNAs could pave the way for the development of novel diagnostic techniques and therapeutic interventions.

Keywords: SASP (senescence-associated secretory phenotype); cellular senescence; extracellular vesicles; microRNAs; type 1 diabetes.

Figure 1

β cell EVs and potential effects of senescence on EV release and cargo. Healthy primary islet β cells release a low quantity of exosomes under typical culture conditions. β cell EVs contain typical EV proteins (Alix, Tsg101, Flotillin-1, CD9, CD81, CD63, Actin, GAPDH), along with autoantigens (GAD65, Proinsulin, ZnT8), and miRNAs (miR-7, miR-21, miR-29, miR-146, miR-155 let-7a, miR-217, miR-223). In contrast, senescent β cells that accumulate during T1D develop a SASP, which we propose involves not only classical SASP factors (SASP soluble factors) but also increased release of EVs (SASP EV release). Senescence may also alter β cell EV cargo, such as increasing the release of autoantigens and changing the miRNA profile. Together these changes in β cell EVs during senescence could facilitate immune signaling and activation events that accelerate the development of T1D.

Figure 2

Therapeutic EV delivery of senotherapeutic miRNAs for improved targeting of SASP in β cells during T1D. The use of specially designed EVs with surface molecules to target β cells (such as GLP1R agonists) and harboring miRNAs to suppress SASP (such as miR-107, miR-183, miR-204, miR-223) could be a powerful approach for improved targeting of SASP⁺ β cells and sparing healthy β cells in vivo during the development of T1D. This approach could downregulate SASP preferentially in β cells, thereby reducing off-target effects of other senotherapeutics and protecting against T1D.