Human umbilical cord mesenchymal stem cells ameliorate erectile dysfunction in rats with diabetes mellitus through the attenuation of ferroptosis

Abstract

Background Erectile dysfunction (ED), as one of the most prevalent consequences in male diabetic patients, has a serious impact on men's physical and mental health, and the treatment effect of diabetic mellitus erectile dysfunction (DMED) is often worse. Therefore, the development of a novel therapeutic approach is urgent. As stem cells with high differentiation potential, human umbilical cord mesenchymal stem cells (HUCMSCs) have been widely used in the treatment of diseases in other systems, and are expected to be a promising strategy for the treatment of DMED. In this study, we investigated the role of HUCMSCs in managing erectile function in rat models of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and compared the effects of two different injection methods. Methods T1DM and T2DM ED rats were given labelled HUCMSCs by corpus cavernosum injection and tail vein injection, respectively. ICP and MAP were monitored simultaneously by electrical stimulation four weeks after injection to indicate the erectile function of rats. To track the development and colonisation capabilities of stem cells, we performed EdU assay with penile tissue. The histological changes of the penis were observed by hematoxylin–eosin staining, and Masson’s trichrome staining was conducted to evaluate the smooth muscle content and the degree of fibrosis in the rat penis. Then, we employed specific kits to measure the level of NO, cGMP, MDA, SOD and Fe in penis. Electron transmission microscopy was implemented to observe morphology of mitochondria. Besides, western blot and immunofluorescence staining were performed to demonstrate the expression of ferroptosis-related genes. Results We found that HUCMSCs improved erectile function in T1DM and T2DM ED rats, with no difference in efficacy between corpus cavernosum injection and tail vein injection. The EdU assay revealed that only a tiny percentage of HUCMSCs colonised the corpus cavernosum, while smooth muscle in the penis expanded and collagen decreased following HUCMSC injection. Moreover, the levels of oxidative stress in the penis of the rats given HUCMSCs were dramatically reduced, as was the tissue iron content. HUCMSCs normalised mitochondrial morphology within corpus cavernosum smooth muscle cells (CCSMCs), which were characteristically altered by high glucose. Furthermore, the expression of ferroptosis inhibitory genes SLC7A11 and GPX4 was obviously elevated in CCSMCs after stem cell management, but the abundances of ACSL4, LPCAT3 and ALOX15 showed the polar opposite tendency. Conclusions HUCMSCs can effectively and safely alleviate erectile dysfunction in T1DM and T2DM ED rats, while restoring erectile function by attenuating diabetes-induced ferroptosis in CCSMCs. Additionally, this study provides significant evidence for the development of HUCMSCs as a viable therapeutic strategy for DMED.

Overexpression of PRDX2 in Adipose-Derived Mesenchymal Stem Cells Enhances the Therapeutic Effect in a Neurogenic Erectile Dysfunction Rat Model by Inhibiting Ferroptosis

“…Recent studies have demonstrated that ferroptosis is related to the OS of CCSMCs in diabetes mellitus-induced ED and that human umbilical cord mesenchymal stem cells could treat diabetes mellitus-induced ED by inhibiting OS via attenuation of ferroptosis [ 36 , 37 ]. Similarly, we were surprised to find that the total iron ( Figure 6(e) ) and MDA ( Figure 6(f) ) contents in the PBS group were significantly higher than those in the sham group ( P < 0.05).…”

“…To further determine whether vehicle-ADSCs and PRDX2-ADSCs had specific inhibitory effects against ferroptosis, we studied the effects of vehicle-ADSCs and PRDX2-ADSCs on RSL3-induced ferroptosis in CCSMCs through a coculture system ( Figure 3(a) ). According to the previous literature and our own experimental results (Figure S1(c) ), the concentration of 0.5 μ M RSL3 was determined to be the appropriate dose for further study [ 36 ]. RSL3, an inhibitor of GPX4, is widely considered an activator of ferroptosis.…”

Stem Cell Therapy for Erectile Dysfunction: A Step towards a Future Treatment

“…Feng et al observed reduced oxidative stress levels and tissue iron content in diabetic rats treated with UCSC with a concomitant overexpression of ferroptosis inhibitory genes SLC7A11 and GPX4. They therefore concluded that stem cell therapy could exert part of its therapeutical effect by attenuation of diabetic-induced ferroptisis [ 39 ]. Similarly, in another diabetic rat model study treated with ADSC designed by Luo et al, a suppression of NLRP3-mediated pyroptosis was observed, suggesting a possible pathogenic mechanism of ED in DM [ 40 ].…”

Elucidating the progress and impact of ferroptosis in hemorrhagic stroke

“…There are numerous ways of catalyzing PEs-AA/ADA to form peroxides ( Kagan et al, 2017 ; Wenzel et al, 2017 ). It has been shown that the rate-limiting steps in acetylation and esterification make ACSL4 and lysophosphatidylcholine acyltransferase 3 (LPCAT3) the critical promoters in the regulation of ferroptosis ( Feng et al, 2022 ). Multiple studies have confirmed the roles of these enzymes.…”