Mesenchymal stem cell with enhanced antioxidant capacity integrates into smooth muscle cells in diabetic detrusor underactivity
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ABSTRACT:
ORGANISM(S): Rattus norvegicus Homo sapiens
PROVIDER: GSE263324 | GEO | 2025/02/17
REPOSITORIES: GEO
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Project description:Diabetic cystopathy, affecting half of individuals with diabetes, often progresses to detrusor underactivity (DUA), a late and irreversible stage of bladder dysfunction. Despite its prevalence, the etiology of diabetic DUA remains elusive, with no established treatments. Mesenchymal stem cell (MSC) transplantation, demonstrated as a promising therapeutic avenue in preclinical studies, lacks comprehensive analyses of its mechanisms, tumorigenic risks, and optimal protocols for diabetic DUA. This study addresses these gaps, exploring transcriptome changes post-MSC treatment in a diabetic DUA preclinical model. Oxidative injury emerged as a significant pathological mechanism, with N-acetylcysteine (NAC) enhancing MSC synergistic effects, potentially reducing the amount of required MSCs . Additionally, human umbilical cord-derived MSCs with high antioxidant capacity (PFO-MSCs) exhibited improved and sustained therapeutic efficacy, integrating into myocytes within bladder muscle bundles or neighboring pericytes. Single-cell transcriptome analysis of engrafted cells revealed expression changes in pathways related to muscle development and immune responses, emphasizing the pivotal roles of cMET and PD-L1 in muscle regeneration and immune modulation within diabetic DUA. This study provides a comprehensive overview of the pathogenesis and repair processes following MSC therapy for diabetic DUA, enhancing our understanding of its mode of action, efficacy, and safety for future clinical applications.
2025-02-17 | GSE263323 | GEO
Project description:Diabetic cystopathy, affecting half of individuals with diabetes, often progresses to detrusor underactivity (DUA), a late and irreversible stage of bladder dysfunction. Despite its prevalence, the etiology of diabetic DUA remains elusive, with no established treatments. Mesenchymal stem cell (MSC) transplantation, demonstrated as a promising therapeutic avenue in preclinical studies, lacks comprehensive analyses of its mechanisms, tumorigenic risks, and optimal protocols for diabetic DUA. This study addresses these gaps, exploring transcriptome changes post-MSC treatment in a diabetic DUA preclinical model. Oxidative injury emerged as a significant pathological mechanism, with N-acetylcysteine (NAC) enhancing MSC synergistic effects, potentially reducing the amount of required MSCs . Additionally, human umbilical cord-derived MSCs with high antioxidant capacity (PFO-MSCs) exhibited improved and sustained therapeutic efficacy, integrating into myocytes within bladder muscle bundles or neighboring pericytes. Single-cell transcriptome analysis of engrafted cells revealed expression changes in pathways related to muscle development and immune responses, emphasizing the pivotal roles of cMET and PD-L1 in muscle regeneration and immune modulation within diabetic DUA. This study provides a comprehensive overview of the pathogenesis and repair processes following MSC therapy for diabetic DUA, enhancing our understanding of its mode of action, efficacy, and safety for future clinical applications.
2025-02-17 | GSE263322 | GEO
Project description:Mesenchymal stem cell with enhanced antioxidant capacity integrates into smooth muscle cells in diabetic detrusor underactivity
| PRJNA1096708 | ENA
Project description:Mesenchymal stem cell with enhanced antioxidant capacity integrates into smooth muscle cells in diabetic detrusor underactivity (Affymetrix)
| PRJNA1096711 | ENA
Project description:Mesenchymal stem cell with enhanced antioxidant capacity integrates into smooth muscle cells in diabetic detrusor underactivity (RNA-Seq)
| PRJNA1096709 | ENA
Project description:Relaxation and contraction of the urinary bladder smooth muscle, also known as the detrusor smooth muscle (DSM), facilitate the micturition cycle. DSM contractility depends on cell excitability, which is established by the synchronized activity of multiple diverse ion channels. K+ channels, the largest family of channels, control DSM excitability by maintaining the resting membrane potential and shaping the action potentials that cause the phasic contractions. Among the members of the voltage-gated K+ (KV) channel superfamily, KV type 7 (KV7) channels — KV7.1–KV7.5 members encoded by KCNQ1–KCNQ5 genes — have been recently identified as functional regulators in various cell types including vascular, cardiac, and neuronal cells. Their regulatory roles in DSM, however, are just now emerging and remain to be elucidated. To address this gap, our research group has initiated the systematic investigation of human DSM KV7 channels in collaboration with clinical urologists. In this comprehensive review, we summarize the current understanding of DSM Kv7 channels and highlight recent discoveries in the field. We describe KV7 channel expression profiles at the mRNA and protein levels, and further elaborate on functional effects of KV7 channel selective modulators on DSM excitability, contractility, and intracellular Ca2+ dynamics in animal species along with in vivo studies and the limited data on human DSM. Within each topic, we highlight the main observations, current gaps in knowledge, and most pressing questions and concepts in need of resolution. We emphasize the lack of systematic studies on human DSM KV7 channels that are now actively ongoing in our laboratory.
| S-EPMC7526500 | biostudies-literature
Project description:Although patients with lower urinary tract symptoms constitute a large and still growing population, understanding of bladder detrusor muscle physiology remains limited. Understanding the interactions between the detrusor smooth muscle cells and other bladder cell types (e.g. interstitial cells, IC) that may significantly contribute to coordinating and modulating detrusor contractions represents a considerable challenge. Computer modeling could help to elucidate some properties that are difficult to address experimentally; therefore, we developed in silico models of detrusor smooth muscle cell and interstitial cells, coupled through gap junctions. The models include all of the major ion conductances and transporters described in smooth muscle cell and interstitial cells in the literature. The model of normal detrusor muscle (smooth muscle cell and interstitial cells coupled through gap junctions) completely reproduced the experimental results obtained with detrusor strips in the presence of several pharmacological interventions (ryanodine, caffeine, nimodipine), whereas the model of smooth muscle cell alone (without interstitial cells) failed to reproduce the experimental results. Next, a model of overactive bladder, a highly prevalent clinical condition in both men and women with increasing incidence at older ages, was produced by modifying several processes as reported previously: a reduction of Ca(2+)-release through ryanodine receptors and a reduction of Ca(2+)-dependent K(+)-conductance with augmented gap junctional coupling. This model was also able to reproduce the pharmacological modulation of overactive bladder. In conclusion, a model of bladder detrusor muscle was developed that reproduced experimental results obtained in both normal and overactive bladder preparations. The results indicate that the non-smooth muscle cells of the detrusor (interstitial cells) contribute significantly to the contractile behavior of bladder detrusor muscle and should not be neglected. The model suggests that reduced Ca(2+)-release through ryanodine receptors and Ca(2+)-dependent K(+)-conductance together with augmented gap junctional coupling might play a major role in overactive bladder pathogenesis.
| S-EPMC5027948 | biostudies-literature
Project description:The aim of our study was to develop a novel approach to investigating mouse detrusor smooth muscle cell (SMC) physiological activity, utilizing an acute tissue dissection technique and confocal calcium imaging. The bladder of a sacrificed adult female NMRI mouse was dissected. We used light and transmission electron microscopy to assess morphology of SMCs within the tissue. Calcium imaging in individual SMCs was performed using confocal microscopy during stimulation with increasing concentrations of carbamylcholine (CCh). SMCs were identified according to their morphology and calcium activity. We determined several parameters describing the SMC responses: delays to response, recruitment, relative activity, and contraction of the tissue. CCh stimulation revealed three different SMC phenotypes: spontaneously active SMCs with and without CCh-enhanced activity and SMCs with CCh-induced activity only. SMCs were recruited into an active state in response to CCh-stimulation within a narrow range (1-25 µM); causing activation of virtually all SMCs. Maximum calcium activity of SMCs was at about 25 µM, which coincided with a visible tissue contraction. Finally, we observed shorter time lags before response onsets with higher CCh concentrations. In conclusion, our novel in situ approach proved to be a robust and reproducible method to study detrusor SMC morphology and physiology.
| S-EPMC7021722 | biostudies-literature
Project description:Mesenchymal stem cells (MSCs) are promising cells to treat cartilage defects due to their chondrogenic differentiation potential. However, an inflammatory environment during differentiation, such as the presence of the cytokine TNFα, inhibits chondrogenesis and limits the clinical use of MSCs. On the other hand, it has been reported that exposure to TNFα during in vitro expansion can increase proliferation, migration, and the osteogenic capacity of MSCs and therefore can be beneficial for tissue regeneration. This indicates that the role of TNFα on MSCs may be dependent on the differentiation stage. To improve the chondrogenic capacity of MSCs in the presence of an inflamed environment, we aimed to determine the effect of TNFα on the chondrogenic differentiation capacity of MSCs. Here, we report that TNFα exposure during MSC expansion increased the chondrogenic differentiation capacity regardless of the presence of TNFα during chondrogenesis and that this effect of TNFα during expansion was reversed upon TNFα withdrawal. Interestingly, pre-treatment with another pro-inflammatory cytokine, IL-1β, did not increase the chondrogenic capacity of MSCs indicating that the pro-chondrogenic effect is specific for TNFα. Finally, we show that TNFα pre-treatment increased the levels of SOX11 and active β-catenin suggesting that these intracellular effectors may be useful targets to improve MSC-based cartilage repair. Overall, these results suggest that TNFα pre-treatment, by modulating SOX11 levels and WNT/β-catenin signaling, could be used as a strategy to improve MSC-based cartilage repair.
| S-EPMC7344141 | biostudies-literature
Project description:Under defined conditions, mesenchymal stem cells can differentiate into unique cell types, making them attractive candidates for cell-based disease therapies. Ischemic diseases would greatly benefit from treatments that include the formation of new blood vessels from mesenchymal stem cells. However, blood vessels are complex structures composed of endothelial cells and smooth muscle cells, and their assembly and function in a diseased environment is reliant upon joining with the pre-existing vasculature. Although endothelial cell/smooth muscle cell interactions are well known, how endothelial cells may influence mesenchymal stem cells and facilitate their differentiation has not been defined. Therefore, we sought to explore how endothelial cells might drive mesenchymal stem cells toward a smooth muscle fate. Our data show that cocultured endothelial cells induce smooth muscle cell differentiation in mesenchymal stem cells. Endothelial cells can promote a contractile phenotype, reduce proliferation, and enhance collagen synthesis and secretion. Our data show that Notch signaling is essential for endothelial cell-dependent differentiation, and this differentiation pathway is largely independent of growth factor signaling mechanisms.
| S-EPMC4201243 | biostudies-literature