NAMPT encapsulated by extracellular vesicles from young adipose-derived mesenchymal stem cells treated tendinopathy in a “One-Stone-Two-Birds” manner

Abstract

Background Tendinopathy is the leading sports-related injury and will cause severe weakness and tenderness. Effective therapy for tendinopathy remains limited, and extracellular vesicles (EVs) derived from adipose tissue-derived mesenchymal stem cells (ADMSCs) have demonstrated great potential in tendinopathy treatment; however, the influence of aging status on EV treatment has not been previously described. Results In this study, it was found that ADMSCs derived from old mice (ADMSCold) demonstrated remarkable cellular senescence and impaired NAD+ metabolism compared with ADMSCs derived from young mice (ADMSCyoung). Lower NAMPT contents were detected in both ADMSCold and its secreted EVs (ADMSCold-EVs). Advanced animal experiments demonstrated that ADMSCyoung-EVs, but not ADMSCold-EVs, alleviated the pathological structural, functional and biomechanical properties in tendinopathy mice. Mechanistic analyses demonstrated that ADMSCyoung-EVs improved cell viability and relieved cellular senescence of tenocytes through the NAMPT/SIRT1/PPARγ/PGC-1α pathway. ADMSCyoung-EVs, but not ADMSCold-EVs, promoted phagocytosis and M2 polarization in macrophages through the NAMPT/SIRT1/Nf-κb p65/NLRP3 pathway. The macrophage/tenocyte crosstalk in tendinopathy was influenced by ADMSCyoung-EV treatment and thus it demonstrated "One-Stone-Two-Birds" effects in tendinopathy treatment. Conclusions This study demonstrates an effective novel therapy for tendinopathy and uncovers the influence of donor age on curative effects by clarifying the detailed biological mechanism. Graphical Abstract

Transcriptome analysis reveals therapeutic potential of NAMPT in protecting against abdominal aortic aneurysm in human and mouse

“…NAMPT is found to circulate both extracellularly in the bloodstream, particularly in plasma and serum, and intracellularly within the cytoplasm, mitochondria, and nucleus of the majority of cells [ [57] , [58] , [59] ]. Substantial evidence suggests that extracellular NAMPT is exclusively present in extracellular vesicles (EVs) in both mice and humans [ 68 ], and the release of NAMPT in EVs under physiological conditions plays a vital role in cellular function [ 69 , 70 ]. NAMPT has the potential to elevate NAD + levels, which can have a positive impact on health and potentially extend lifespan [ 69 ].…”

“…Thus, compared to various interventions, such as CTRP13 [ 56 ] and Niacin [ 53 ]. Our approach is notably more direct and advantageous for several reasons: (1) NAMPT can circulate both within the bloodstream, specifically in plasma and serum, and intracellularly within the cytoplasm, mitochondria, and nucleus of various cell types [ [57] , [58] , [59] ]; (2) A wealth of evidence indicates that extracellular NAMPT is exclusively packaged within EVs in both mice and humans [ 68 ]; (3) The release of NAMPT within extracellular vesicles under physiological conditions plays a pivotal role in modulating cellular functions [ 69 , 70 ]. By harnessing the capacity to load NAMPT into EVs, we aim to faithfully replicate physiological conditions in humans, thereby offering a more promising avenue for therapy.…”

Biodelivery of therapeutic extracellular vesicles: should mononuclear phagocytes always be feared?

“…After local administration, MSC-derived EVs containing therapeutic miRNAs may promote M2 macrophage-mediated angiogenesis and tendon regeneration after its rapture ( Xu et al, 2023 ). Additionally, EVs isolated from adipose tissue-derived MSCs ameliorated tendinopathy by promoting phagocytosis and M2 polarization of macrophages ( Wu et al, 2023 ). Furthermore, stimulating M2 macrophage phenotype by MSC-derived EVs may also improve ligament healing ( Chamberlain et al, 2021 ).…”

Therapeutic Potential of Exosomes in Tendon and Tendon–Bone Healing: A Systematic Review of Preclinical Studies

“…It is significant to point out that current methods for exosome purification are immature and imperfect. Sometimes, other types of extracellular vesicles are present in purified exosomes, resulting in a diameter distribution that is not completely contained within the range of 30~150 nm [ 47 , 48 , 51 , 61 , 62 , 71 , 74 , 78 , 98 , 99 , 100 ]. So, for articles that focus on the effect of extracellular vesicles promoting tendon or tendon–bone healing, we examined the distribution of extracellular vesicle diameters.…”