Abstract
BackgroundChronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is an intractable nonbacterial inflammatory disease. Mesenchymal stem cells (MSCs) derived from human induced pluripotent stem cells (hiPSCs, iMSCs) have been well documented for the management of inflammatory and autoimmune disorders because of their powerful immunoregulatory and anti-inflammatory capacities. Recently, studies have indicated that extracellular vesicles (EVs) released from iMSCs hold biological functions similar to their parental cells. This study aimed to evaluate the therapeutic efficacy of EVs released from iMSCs (iMSCs-EVs) on CP/CPPS and to explore the underlying mechanisms.MethodsAn experimental autoimmune prostatitis (EAP) model was established in rats by subcutaneous injection of prostate antigen with adjuvant. Then, iMSCs-EVs were injected into EAP rats via the tail vein. Pain behavioral measurements, urodynamic tests, and histopathological analyses were performed at 2, 4, and 6 weeks. The expression of cyclooxygenase-2 (COX-2) was evaluated by immunofluorescence staining and Western blot. The alterations of B cells, Th1 cells, Th2 cells, Th17 cells, and Treg cells in peripheral blood and spleen were analyzed using flow cytometry. The levels of Th1-, Th2-, Th17-, and Treg-related inflammatory mediators were determined by ELISA.ResultsAfter iMSCs-EVs administration, rats had reduced pain as indicated by the recovery of nociceptive responses to baseline. The voiding pressure was significantly reduced, and the intercontraction interval was increased. The findings of histopathological analysis revealed that iMSCs-EVs could significantly decrease inflammatory cell infiltration and promote basal lamina and glandular epithelial tissue repair. Further studies demonstrated that the overexpression of COX-2 was downregulated by iMSCs-EVs. Meanwhile, the increases in the percentages of Th1 and Th17 cells were dramatically reversed. Also, rats that received iMSCs-EVs showed markedly increased percentages of Treg cells. The levels of those inflammatory mediators showed the same changing tendency.ConclusionsiMSCs-EVs administration has the potential to ameliorate chronic pelvic pain, improve voiding dysfunction, suppress inflammatory reactions, and facilitate prostatic tissue repair. The functions are mediated by downregulating the overexpression of COX-2 and restoring the imbalance of Th1/Th2 and Treg/Th17 cells.
Highlights
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is an intractable nonbacterial inflammatory disease
Further studies demonstrated that the overexpression of COX-2 was downregulated by iMSCs-extracellular vesicles (EVs)
The findings demonstrated that iMSCs strongly expressed pluripotency-related surface markers including CD44, CD73, CD90, and CD105, but not CD11b, CD19, CD34, CD45, and HLA-DR- (Fig. 1a)
Summary
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is an intractable nonbacterial inflammatory disease. Studies have indicated that extracellular vesicles (EVs) released from iMSCs hold biological functions similar to their parental cells. Chronic prostatitis/chronic pelvic pain syndrome (CP/ CPPS) remains the most challenging andrological dilemma in male patients younger than 50 years, accounting for more than 90–95% of prostatitis diagnoses [1, 2]. This type of prostatitis is defined as chronic pelvic pain and symptoms of prostate inflammation lasting at least 3 to 6 months in the absence of any detectable infectious agents [3]. It is imperative to develop an effective therapeutic strategy
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