Background: Endothelial progenitor cells (EPCs) can be used to treat ischemic disease in cell-based therapy owing to their neovascularization potential. Glucocorticoids (GCs) have been widely used as strong anti-inflammatory reagents. However, despite their beneficial effects, side effects, such as impairing wound healing are commonly reported with GC-based therapy, and the effects of GC therapy on the wound healing function of EPCs are unclear.Methods: In this study, we investigated how GC treatment affects the characteristics and wound healing function of EPCs.Results: We found that GC treatment reduced the proliferative ability of EPCs. In addition, the expression of CXCR4 was dramatically impaired, which suppressed the migration of EPCs. A transplantation study in a flap mouse model revealed that GC-treated EPCs showed a poor homing ability to injured sites and a low activity for recruiting inflammatory cells, which led to wound healing dysfunction. Impairment of prostaglandin E2 (PGE2) synthases, cyclooxygenase (COX2) and microsomal PGE2 synthase 1 (mPEGS1) were identified as being involved in the GC-induced impairment of the CXCR4 expression in EPCs. Treatment with PGE2 rescued the expression of CXCR4 and restored the migration ability of GC-treated EPCs. In addition, the PGE2 signal that activated the PI3K/AKT pathway was identified to be involved in the regulation of CXCR4 in EPCs under the effects of GCs. In addition, similar negative effects of GCs were observed in EPCs under hypoxic conditions. Under hypoxic conditions, GCs independently impaired the PGE2 and HIF2α pathways, which downregulated the expression of CXCR4 in EPCs. Our findings highlighted the influences of GCs on the characteristics and functions of EPCs, suggesting that the use of EPCs for autologous cell transplantation in patients who have used GCs for a long time should be considered carefully.
Cytokine storm is recognized as one of the factors contributing to organ failures and mortality in patients with COVID-19. Due to chronic inflammation, COVID-19 patients with diabetes mellitus (DM) or renal disease (RD) have more severe symptoms and higher mortality. However, the factors that contribute to severe outcomes of COVID-19 patients with DM and RD have received little attention. In an effort to investigate potential treatments for COVID-19, recent research has focused on the immunomodulation functions of mesenchymal stem cells (MSCs). In this study, the correlation between DM and RD and the severity of COVID-19 was examined by a combined approach with a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that the odd of mortality in patients with both DM and RD was increased in comparison to those with a single comorbidity. In addition, in the experimental research, the data showed that high glucose and uremic toxins contributed to the induction of cytokine storm in human lung adenocarcinoma epithelial cells (Calu-3 cells) in response to SARS-CoV Peptide Pools. Of note, the incorporation of Wharton's jelly MSC-derived extracellular vesicles (WJ-EVs) into SARS-CoV peptide-induced Calu-3 resulted in a significant decrease in nuclear NF-kB p65 and the downregulation of the cytokine storm under high concentrations of glucose and uremic toxins. This clearly suggests the potential for WJ-EVs to reduce cytokine storm reactions in patients with both chronic inflammation diseases and viral infection.
Cancer metastasis is the leading cause of mortality among breast cancer patients. Type 2 diabetes mellitus (T2DM) has been suggested as a risk factor of breast cancer; however, whether or not T2DM is associated with breast tumor metastasis remains unclear. In this study, we examined the involvement of T2DM with breast cancer metastasis by a combined approach of a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that diabetes significantly increases the risk of lymph node metastasis by 1.10-fold (P < 0.01). Consistently, our data from experimental research showed that T2DM induced paracrine effects of mesenchymal stem cells (MSCs), a key contributor to cancer progression, to stimulate metastasis of breast cancer cells (BCCs) by two independent mechanisms. First, T2DM induced the excess secretion of interleukin 6 (IL6) from MSCs, which activated the JAK/STAT3 pathway in BCCs, thus promoting the metastasis of BCCs. Second, beside the EGR-1-/IL6-dependent mechanism, T2DM altered the functions of MSC-derived extracellular vesicles (EVs), which are highly associated with the metastasis of BCCs. Our present study showed that T2DM is a risk factor for breast cancer metastasis, and MSC-derived EVs might be useful for developing a novel anti-breast cancer therapy strategy.
Aging induces numerous cellular disorders, such as the elevation of reactive oxygen species (ROS), in a number type of cells, including mesenchymal stem cells (MSCs). However, the correlation of ROS and impaired healing abilities as well as whether or not the inhibition of elevating ROS results in the rejuvenation of elderly MSCs is unclear. The rejuvenation of aged MSCs has thus recently received attention in the field of regenerative medicine. Specifically, extracellular vesicles (EVs) act as a novel tool for stem cell rejuvenation due to their gene transfer ability with systemic effects and safety. In the present study, we examined the roles of aging-associated ROS in the function and rejuvenation of elderly MSCs by infant EVs. The data clearly showed that elderly MSCs exhibited the downregulation of superoxide dismutase (SOD)1 and SOD3, which resulted in the elevation of ROS and downregulation of the MEK/ERK pathways, which are involved in the impairment of the MSCs’ ability to decrease necrotic area in the skin flap model. Furthermore, treatment with the antioxidant Edaravone or co-overexpression of SOD1 and SOD3 rescued elderly MSCs from the elevation of ROS and cellular senescence, thereby improving their functions. Of note, infant MSC-derived EVs rejuvenated elderly MSCs by inhibiting ROS production and the acceleration of cellular senescence and promoting the proliferation and in vivo functions in both type 1 and type 2 diabetic mice.
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