Extracellular vesicles in β cell biology: Role of lipids in vesicle biogenesis, cargo, and intercellular signaling

Aguirre, Rebecca Schneider; Kulkarni, Abhishek; Becker, Matthew W.; Lei, Xiaoyong; Sarkar, Soumyadeep; Ramanadham, Sasanka; Phelps, Edward A.; Nakayasu, Ernesto; Sims, Emily K.; Mirmira, Raghavendra G.

doi:10.1016/j.molmet.2022.101545

Cited by 12 publications

(10 citation statements)

References 221 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Microvesicles are 100 to 1000 nm in diameter and formed by directly budding from the plasma membrane. Apoptotic bodies are larger EVs (>1000 nm) formed by blebbing of cells undergoing apoptosis (Aguirre et al , 2022; Raposo & Stoorvogel, 2013; Salomon et al , 2022). EVs have immense potential as biomarkers as they can carry signatures of the tissues of origin and processes affected by disease (Salomon et al ., 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Our team has been interested on understanding the roles of EVs in type 1 diabetes (T1D) development and their potential as biomarkers of the disease, as we recently discussed in a review article (Aguirre et al ., 2022). It has been shown that EVs carry molecules, such as microRNAs and chemokines that induces β-cell apoptosis (Javeed et al , 2021; Lakhter et al , 2018; Zhu et al , 2022).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Meta-analysis refinement of plasma extracellular vesicle composition identifies proplatelet basic protein as a signaling messenger in type 1 diabetes

Vallejo

Sarkar

Elliott

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Extracellular vesicles (EVs) play important roles in cell-to-cell communication and are potential biomarkers as they carry markers of their derived tissues and disease signatures. However, obtaining pure EV preparations from biofluids is challenging due to contaminants with similar physicochemical properties. Here, we performed a meta-analysis of plasma EV proteomics data deposited in public repositories to refine the protein composition of EVs and investigate potential roles in type 1 diabetes development. With the concept that each purification method yields different proportions of distinct contaminants, we grouped proteins into clusters based on their abundance profiles. This allowed us to separate clusters with classical EV markers, such as CD9, CD40, C63 and CD81, from clusters of well-known contaminants, such as serum albumin, apolipoproteins and components of the complement and coagulation pathways. Two clusters containing a total of 1720 proteins combined were enriched with EV markers and depleted in common contaminants; therefore, they were considered to contain bona fide EV components. As possible origins of plasma EVs, these clusters had markers of tissues such as spleen, liver, brain, lungs, pancreas, and blood/immune cells. These clusters were also enriched in cell surface markers CD antigens, and proteins from cell-to-cell communication and signaling pathways, such as chemokine signaling and antigen presentation. We also show that the EV component and type 1 diabetes biomarker, platelet basic protein (PPBP/CXCL7) regulates apoptosis in both beta and macrophage cell lines. Overall, our meta-analysis refined the composition of plasma EVs, reinforcing a primary function as messengers for cell-to-cell communication and signaling. Furthermore, this analysis identifies optimal avenues to target EVs for development of disease biomarkers.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Meta-analysis refinement of plasma extracellular vesicle composition identifies proplatelet basic protein as a signaling messenger in type 1 diabetes

Vallejo

Sarkar

Elliott

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…We tried to address this by isolating by size and specific membrane components to more selectively isolate subpopulations, and validation of isolations with multiple techniques. However, our preparations likely still contained a combination of EVs derived from the MVE or exosomes and microvesicles, which are classically derived from membrane blebbing (5). Plasma sample analysis was limited by available blood volume, and included systemic EVs from multiple cell types, therefore the relative contribution of β cell EVs was likely limited, especially considering reduced β cell mass in children with T1D.…”

Section: Discussionmentioning

confidence: 99%

“…Extracellular vesicles (EVs) are membrane bound nanoparticles housing molecular cargo (5). EVs can be transferred to or interact with other cells as a means of cell:cell communication (6–8).…”

Section: Introductionmentioning

confidence: 99%

Proinflammatory stress activates neutral sphingomyelinase 2 based generation of a ceramide-enriched β cell EV subpopulation

Xu,

Harris-Kawano,

Enriquez

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

β cell extracellular vesicles (EVs) play a role as paracrine effectors in islet health, yet mechanisms connecting β cell stress to changes in EV cargo and potential impacts on diabetes remain poorly defined. We hypothesized that β cell inflammatory stress engages neutral sphingomyelinase 2 (nSMase2)-dependent EV formation pathways, generating ceramide-enriched EVs that could impact surrounding β cells. Consistent with this, proinflammatory cytokine treatment of INS-1 β cells and human islets concurrently increased β cell nSMase2 and ceramide expression, as well as EV ceramide staining. Direct chemical activation or genetic knockdown of nSMase2, or treatment with a GLP-1 receptor agonist also modulated cellular and EV ceramide. Small RNA sequencing of ceramide-enriched EVs identified a distinct set of miRNAs linked to β cell function and identity. Coculture experiments using CD9-GFP tagged INS-1 cell EVs demonstrated that either cytokine treatment or chemical nSMase2 activation increased EV transfer to recipient cells. Children with recent-onset T1D showed no abnormalities in circulating ceramide-enriched EVs, suggesting a localized, rather than systemic phenomenon. These findings highlight nSMase2 as a regulator of β cell EV cargo and identify ceramide-enriched EV populations as a contributor to EV-related paracrine signaling under conditions of β cell inflammatory stress.

show abstract

“…Another outcome of ISR activation is the formation of nonmembranous stress granules that consist of translationally repressed mRNA and associated RNA-binding proteins ( 59 ). Because stress granules can also be released as extracellular vesicle contents ( 60–62 ), their contents could serve as a means of β-cell-to-immune cell communication in T1D ( 63 ). Under normal conditions, stress granule formation is reversible.…”

Section: Integrated Stress Responsementioning

confidence: 99%

Inside the β Cell: Molecular Stress Response Pathways in Diabetes Pathogenesis

et al. 2022

Self Cite

View full text Add to dashboard Cite

The pathogeneses of the two major forms of diabetes, type 1 and type 2, differ with respect to their major molecular insults (loss of immune tolerance and onset of tissue insulin resistance, respectively). However, evidence suggests that dysfunction and/or death of insulin-producing β-cells is common to virtually all forms of diabetes. Although the mechanisms underlying β-cell dysfunction remain incompletely characterized, recent years have been witness to major advances in our understanding of the molecular pathways that contribute to the demise of the β-cell. Cellular and environmental factors contribute to β-cell dysfunction/loss through the activation of molecular pathways that exacerbate endoplasmic reticulum stress, the integrated stress response, oxidative stress, and impaired autophagy. Whereas many of these stress responsive pathways are interconnected, their individual contributions to glucose homeostasis and β-cell health have been elucidated through the development and interrogation of animal models. In these studies, genetic models and pharmacological compounds have enabled the identification of genes and proteins specifically involved in β-cell dysfunction during diabetes pathogenesis. Here, we review the critical stress response pathways that are activated in β-cells in the context of the animal models.

show abstract

Extracellular vesicles in β cell biology: Role of lipids in vesicle biogenesis, cargo, and intercellular signaling

Cited by 12 publications

References 221 publications

Meta-analysis refinement of plasma extracellular vesicle composition identifies proplatelet basic protein as a signaling messenger in type 1 diabetes

Meta-analysis refinement of plasma extracellular vesicle composition identifies proplatelet basic protein as a signaling messenger in type 1 diabetes

Proinflammatory stress activates neutral sphingomyelinase 2 based generation of a ceramide-enriched β cell EV subpopulation

Inside the β Cell: Molecular Stress Response Pathways in Diabetes Pathogenesis

Contact Info

Product

Resources

About