Rapid and Widespread Distribution of Intranasal Small Extracellular Vesicles Derived from Mesenchymal Stem Cells throughout the Brain Potentially via the Perivascular Pathway
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PROVIDER: S-EPMC10675165 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Aging is associated with high prevalence of chronic degenerative diseases that take a large part of the increasing burden of morbidities in a growing demographic of elderly people. Aging is a complex process that involves cell autonomous and cell non-autonomous mechanisms where senescence plays an important role. Senescence is characterized by the loss of proliferative potential, resistance to cell death by apoptosis and expression of a senescence-associated secretory phenotype (SASP). SASP includes pro-inflammatory cytokines and chemokines, tissue-damaging proteases, growth factors; all contributing to tissue microenvironment alteration and loss of tissue homeostasis. Emerging evidence suggests that the changes in the number and composition of extracellular vesicles (EVs) released by senescent cells contribute to the adverse effects of senescence in aging. In addition, age-related alterations in mesenchymal stem/stromal cells (MSCs) have been associated to dysregulated functions. The loss of functional stem cells necessary to maintain tissue homeostasis likely directly contributes to aging. In this review, we will focus on the characteristics and role of EVs isolated from senescent MSCs, the potential effect of MSC-derived EVs in aging and discuss their therapeutic potential to improve age-related diseases.
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Project description:Antiangiogenic tyrosine kinase inhibitors (AA-TKIs) have become a promising therapeutic strategy for colorectal cancer (CRC). In clinical practice, a significant proportion of cancer patients temporarily discontinue AA-TKI treatment due to recurrent toxicities, economic burden or acquired resistance. However, AA-TKI therapy withdrawal-induced tumour revascularization frequently occurs, hampering the clinical application of AA-TKIs. Here, this study demonstrates that tumour perivascular cells mediate tumour revascularization after withdrawal of AA-TKI therapy. Pharmacological inhibition and genetic ablation of perivascular cells largely attenuate the rebound effect of CRC vascularization in the AA-TKI cessation experimental settings. Mechanistically, tumour perivascular cell-derived extracellular vehicles (TPC-EVs) contain Gas6 that instigates the recruitment of endothelial progenitor cells (EPCs) for tumour revascularization via activating the Axl pathway. Gas6 silence and an Axl inhibitor markedly inhibit tumour revascularization by impairing EPC recruitment. Consequently, combination therapy of regorafenib with the Axl inhibitor improves overall survival in mice metastatic CRC model by inhibiting tumour growth. Together, these data shed new mechanistic insights into perivascular cells in off-AA-TKI-induced tumour revascularization and indicate that blocking the Axl signalling may provide an attractive anticancer approach for sustaining long-lasting angiostatic effects to improve the therapeutic outcomes of antiangiogenic drugs in CRC.
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Project description:Traumatic brain injury (TBI) is a leading cause of disability in adults, significantly affecting patients' quality of life. Extracellular vesicles (EVs) derived from human adipose-derived mesenchymal stem cells (hADSCs) have demonstrated therapeutic potential in TBI treatment. However, their limited targeting ability, short half-life, and low bioavailability present significant challenges for clinical application. In this study, we engineered extracellular vesicles (EEVs) by transfecting hADSCs with lentivirus and incorporating ultra-small paramagnetic nanoparticles (USPNs), resulting in EVs with enhanced miRNA expression and targeted delivery capabilities. These EEVs were administered intranasally to specifically target injury sites, effectively modulating the NF-κB signaling pathway to suppress neuroinflammation. In both in vitro and in vivo assessments, EEVs exhibited superior efficacy in promoting neurofunctional recovery and neurogenesis after brain injury compared to unmodified EVs. Furthermore, validation using human brain organoid models confirmed EEVs' remarkable ability to suppress neuroinflammation, offering a promising strategy for TBI treatment.
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