Extracellular Vesicles from Adipose Tissue Stem Cells in Diabetes and Associated Cardiovascular Disease; Pathobiological Impact and Therapeutic Potential

Abstract

Adipose tissue-derived stem cells (ADSCs) are pluripotent mesenchymal stem cells found in relatively high percentages in the adipose tissue and able to self-renew and differentiate into many different types of cells. “Extracellular vesicles (EVs), small membrane vesicular structures released during cell activation, senescence, or apoptosis, act as mediators for long distance communication between cells, transferring their specific bioactive molecules into host target cells”. There is a general consensus on how to define and isolate ADSCs, however, multiple separation and characterization protocols are being used in the present which complicate the results’ integration in a single theory on ADSCs’ and their derived factors’ way of action. Metabolic syndrome and type 2 diabetes mellitus (T2DM) are mainly caused by abnormal adipose tissue size, distribution and metabolism and so ADSCs and their secretory factors such as EVs are currently investigated as therapeutics in these diseases. Moreover, due to their relatively easy isolation and propagation in culture and their differentiation ability, ADSCs are being employed in preclinical studies of implantable devices or prosthetics. This review aims to provide a comprehensive summary of the current knowledge on EVs secreted from ADSCs both as diagnostic biomarkers and therapeutics in diabetes and associated cardiovascular disease, the molecular mechanisms involved, as well as on the use of ADSC differentiation potential in cardiovascular tissue repair and prostheses.

Adipose Stromal/Stem Cell-Derived Extracellular Vesicles: Potential Next-Generation Anti-Obesity Agents

“…In particular, ASC-EVs could be exploited as a diagnostic tool for the assessment of obesity and the related metabolic complications. In fact, EVs from obese patients are characterized by the presence of specific biomarkers in their content, such as perilipin A, which is associated with insulin resistance, or cystatin C and CD14, which are associated with cardiovascular complications (reviewed in [93]).…”

“…EV use for diagnostic purposes [92,93] Methods of EV isolation are not yet fully standardized [98] Good handling [98] EVs' storage stability is not well known [98] Small size precluding pulmonary embolism if administered in a large number and favoring crossing of the BBB [99,100] The age of tissue/cell donors influences the number of ASCs, and thereby EVs, obtainable from SAT, even though the results are still conflicting [44,75,101] Low/null expression of membrane histocompatibility markers, reducing the risk of host immune responses [99] Weight of donors and the presence of metabolic pathologies can alter EVs' quality/characteristics [29,101,102] EVs carry only a fraction of the molecules produced by the cells of origin, favoring selection for specific therapeutic purposes [100] Restriction in the range of products donated by EVs compared with entire MSCs, so that the therapeutic dose and efficacy of EVs must still be clearly defined [92] Homing certain tissues depends on their source tissue, which would be mainly useful in the case of the use of EV for targeted drug delivery [33] It is not clear how extensive the EV homing ability is. [33] EVs, similar to iPSCs and unlike MSCs, should not be tumorigenic and, in selected cases, could also serve as a new anticancer tool [103][104][105] Data are still conflicting.…”

Aortic valve disease in diabetes: Molecular mechanisms and novel therapies

“…There is evidence of the potential role of ADSC-derived EVs in different pathologic conditions, either as biomarkers or as a direct effector or as a delivery system to target miRNAs to cells. 79 Finally, to find relevant targets for therapy, new animal models 96,97 which could recapitulate the evolution of human AV disease need to be developed. Once obtained, the newly found therapeutical targets need to be further validated in 3D-human aortic valve models, 64,98 as well as in large animals, for evaluation of safety and efficacy, before testing in clinical trials.…”

“…Currently, extracellular vehicles (EV) derived from ADSCs emerge as both diagnostic biomarkers and therapeutic tools in diabetes. 79 …”

“…There is evidence of the potential role of ADSC‐derived EVs in different pathologic conditions, either as biomarkers or as a direct effector or as a delivery system to target miRNAs to cells. 79 …”