Search Results (615)

Inhibition of Wnt/β-catenin signaling differentiates mesenchymal stem cells (MSCs) into hepatocytes. However, there is lack of data on whether transplanting these cells can enhance liver regeneration. Additionally, it remains unknown if the flavonoids quercetin and rutin and the clinically used drug lithium chloride (LiCl) can effectively differentiate MSCs into hepatocytes and promote liver regeneration. To address this, the rat bile duct ligation (BDL) fibrosis model was used. Male Wistar rats were surgically ligated. Liver function tests, histological analysis and cell tracking were also conducted to validate liver regeneration. Treatment with quercetin inhibited the Wnt pathway, while rutin and LiCl activated it. Hepatic differentiation was noted in three treatment groups: quercetin, quercetin with rutin and LiCl. We observed that the initial downregulation of the Wnt pathway, followed by its upregulation, facilitated the differentiation of MSCs into hepatocytes. Transplantation of quercetin-treated MSC-derived hepatocytes into the rat BDL fibrosis model resulted in complete restoration of liver function, normalization of elevated systemic liver enzymes and reduction of inflammation and fibrosis. Interestingly, quercetin-treated hepatocytes resulted in enhanced liver regeneration compared to rutin and LiCl. Finally, tracking of labeled hepatocytes confirmed their main localization in the liver. In conclusion, MSC-derived hepatocytes, generated through ex vivo treatment with quercetin, exhibit enhanced liver regeneration. These findings provide a novel ex vivo treatment strategy with flavonoids and the clinically used drug LiCl to achieve enhanced liver regeneration in vivo. Full article

Progressive bladder fibrosis and impaired detrusor function represent converging pathological endpoints across diverse bladder disorders, including bladder outlet obstruction (BOO) associated with benign prostatic hyperplasia, spinal cord injury (SCI)-induced neurogenic bladder, radiation cystitis, and interstitial cystitis/bladder pain syndrome. Conventional therapies primarily manage symptoms and rarely reverse established fibrosis or restore durable bladder homeostasis. Mesenchymal stem/stromal cells (MSCs) have attracted considerable interest as therapeutic agents owing to their antifibrotic, immunomodulatory, angiogenic, and trophic paracrine activities. This review synthesises six key studies from our group and places them within the broader international literature on bladder regenerative medicine: (i) feasibility of superparamagnetic iron oxide (SPIO)-based molecular MRI tracking of transplanted human MSCs (hMSCs) in the bladder; (ii) SPIO-hMSC therapy for BOO-associated fibrosis with concurrent MRI monitoring; (iii) hepatocyte growth factor (HGF)-overexpressing engineered hMSC (B10.HGF) therapy in BOO; (iv) hMSC transplantation into the SCI-injured bladder wall monitored by MRI; (v) systematic review and meta-analysis of stem cell therapy effects on urodynamic outcomes in SCI models; and (vi) HGF-overexpressing hMSC therapy for BOO-induced underactive bladder. These six key studies are contextualised within the broader literature addressing cell sources, biomaterial-assisted delivery platforms, mechanistic pathways, emerging clinical evidence, and the evolving regulatory landscape for cell-based advanced therapy medicinal products. Key translational challenges include product standardisation, long-term durability, and mechanism-linked potency assay development. Full article

Intraperitoneal (I.P.) delivery of cell-based therapeutics represents a promising strategy for treating regional peritoneal diseases; however, rapid cellular clearance severely limits therapeutic durability. A critical unmet need is the development of implantable biomaterial platforms that can both mechanically integrate within the dynamic I.P. cavity and sustain viable cell persistence in vivo. Here, we establish a Continuous Liquid Interface Production (CLIP)-based 3D bioprinting strategy to engineer transplantable, cell-laden hydrogel scaffolds optimized for I.P. implantation. Through systematic bioresin design, we identify a GelMA-PEGDA formulation that achieves a balance between high-resolution printability, tissue-matched mechanical characteristics (Young’s modulus 10–15 kPa), and controlled biodegradation (~75% mass loss over 14 days). The resulting constructs support sustained cell viability and proliferation for over 30 days in vitro. Importantly, in an animal study conducted in 6–8 weeks of female nude mice, in vivo I.P. implantation demonstrates a ~10-fold extension in cellular persistence compared to direct cell injection, prolonging the time to 50% signal decay from ~3 days to ~30 days, with detectable cell retention approaching two months in select animals. The platform further accommodates multiple clinically relevant cell types, including human mesenchymal stem cells and neural stem cells, highlighting its translational versatility. Collectively, this work defines key material and architectural parameters required for I.P. implantable cell therapeutics and establishes CLIP-based bioprinting as a scalable strategy for regional delivery of living therapeutics. Full article

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease with limited therapeutic options. Ferroptosis contributes to renal tubular injury in DN. This study investigates whether mesenchymal stem cells (MSCs) ameliorate DN by inhibiting ferroptosis and elucidates the underlying mechanism. In a rat model of type 2 DN, MSCs transplantation improved renal function and histopathology, while reducing mitochondrial dysfunction, iron overload, and ROS-driven ferroptosis. In vitro, MSCs reversed high glucose-induced ferroptosis hallmarks in tubular epithelial cells. Mechanistically, RNA sequencing identified the MAPK/ERK pathway as key. MSCs suppressed the p-ERK/ERK-GPX4/ACSL4 axis, preventing glutathione depletion and lipid peroxidation. Activation of ERK abolished MSCs’ protection, whereas ERK inhibition mimicked it. These findings reveal that targeting ERK-mediated ferroptosis in renal tubules offers a novel therapeutic strategy, with MSCs acting through this specific mechanism. Full article

Pulmonary arterial hypertension (PAH) is a chronic and progressive cardiopulmonary vascular disorder associated with poor clinical prognosis. Its hallmark pathological feature is sustained elevation of pulmonary vascular resistance resulting from extensive vascular remodeling. Endothelial-to-mesenchymal transition (EndMT), a critical event driving vascular remodeling, is increasingly recognized as central to PAH development and progression. This review systematically outlines the convergence of multiple pathophysiological insults on endothelial dysfunction and intimal remodeling in PAH, highlighting their roles in initiating EndMT. Principal factors include: (1) genetic and molecular alterations, such as BMPR2 mutations and epigenetic dysregulation; (2) environmental and toxic exposures, including chronic hypoxia and anorexigens; (3) inflammatory and immune dysregulation, exemplified by chronic inflammatory infiltrates and autoimmune conditions; and (4) hemodynamic and metabolic disturbances, notably aberrant shear stress and lipid metabolic imbalance. Given the critical contribution of EndMT to PAH pathogenesis, therapeutic strategies aimed at reversing EndMT represent promising anti-remodeling interventions. Preclinical studies have begun exploring EndMT-targeted therapies, including mesenchymal stem cell (MSC) transplantation and dipeptidyl peptidase-4 (DPP-4) inhibitors. Herein, we summarize recent advances regarding EndMT in PAH, dissect the molecular drivers and modulators initiating and sustaining EndMT, and critically evaluate emerging therapeutic strategies harnessing this pathway for clinical benefit. Full article

The treatment of full-thickness skin defects remains a major challenge in clinical medicine. Accelerating wound healing and promoting the restoration of tissue function are of paramount importance. Stem cell therapy has been applied in clinical practice to facilitate wound repair. However, the low survival rate of transplanted stem cells in an ischemic and hypoxic microenvironment severely limits the effectiveness of their clinical application. Microspheres, owing to their excellent biocompatibility and drug delivery capabilities, can serve as effective carriers for oxygen transport. It is worthwhile to evaluate the timing and process of oxygen release under hypoxic conditions. In this study, core–shell structured oxygen-releasing microspheres were prepared and incorporated with the photosensitizer hypericin (HYP) to enable dynamic tracking of the oxygen release process via fluorescent signals. The effects of the oxygen-releasing microspheres on cells under hypoxic conditions were analyzed, focusing primarily on the characterization of the microspheres, their biocompatibility, luminescent properties, and oxygen-releasing capacity. Furthermore, the efficacy of the oxygen-releasing microspheres in combination with bone marrow mesenchymal stem cells (BMSCs) in promoting wound healing was evaluated in vivo. The results indicate that the addition of the microspheres improved cell survival rates in hypoxic environments; meanwhile, their luminescent properties demonstrated the potential of fluorescence intensity as a visual indicator of oxygen release. Full article

Post-stroke depression (PSD) is the most prevalent neuropsychological disorder among stroke survivors, affecting over 30% of patients. It significantly impairs patients’ quality of life and imposes a substantial burden on individuals, families, and society. Currently, the primary treatment for PSD focuses on conventional antidepressant therapies, with a lack of innovative approaches. Therefore, there is an urgent need to develop novel targeted therapies for PSD. This review synthesizes PSD pathogenesis as a multi-system network disorder involving monoamine deficits, neuroinflammation, HPA axis dysfunction, and neurotrophic imbalance. Within this framework, mesenchymal stem cells (MSCs) transplantation, as an emerging therapeutic strategy, may exert beneficial effects through anti-inflammatory, neuroprotective mechanisms, and the provision of neurotrophic factors. This review provides a preclinical framework that highlights the potential of MSC-based strategies, while emphasizing the need for further validation in PSD-specific models before clinical translation. Full article

Diabetes mellitus is a chronic and progressive metabolic disorder associated with abnormal blood glucose levels. The term involves several diseases with different pathophysiology mechanisms and treatment strategies. Stem cell-based treatments represent an emerging strategy for patients with diabetes mellitus with severe pancreatic insufficiency and poor glycemic control. Over the last 20 years, researchers have investigated mesenchymal stem cell infusion and the transplantation of stem cell-derived β cells and islet tissues. This review aims to comprehensively discuss the latest advances in the field of stem cell use in diabetes, including clinical studies and preclinical experiments aiming at improving the efficacy and safety of stem cell use. Full article

Mesenchymal stem/stromal cells (MSCs) are multipotent progenitor cells with potent immunomodulatory properties, making them attractive candidates for treating inflammatory and autoimmune diseases. A key mediator of MSC-induced immunosuppression is programmed death-ligand 1 (PD-L1), a checkpoint molecule that interacts with PD-1 on immune cells to regulate immune responses and promote tolerance. This review synthesizes current evidence on the role of PD-L1 expression in MSCs, emphasizing its effects on both the innate and adaptive immune systems, its therapeutic potential, and its utility as a biomarker for MSC potency and clinical efficacy. We examine how PD-L1 modulates T cell activation, dendritic cell maturation, macrophage polarization, and cytokine profiles, including its role in exosomal contexts. Additionally, we highlight its synergistic interactions with other immune checkpoints and discuss its dual function as both a therapeutic effector and a dynamic biomarker. Finally, we explore its relevance in clinical contexts such as autoimmune diseases, graft-versus-host disease, sepsis, and transplantation and conclude with a discussion of challenges and future directions in harnessing PD-L1 for MSC-based therapies. Full article

Ovarian dysfunction resulting from metabolic or toxic injury is characterized by follicular depletion, stromal remodeling, oxidative stress, and endocrine dysregulation. Placenta-derived mesenchymal stem cells (PD-MSCs) have been proposed as a potential therapeutic approach due to their paracrine factors, including placental growth factor (PlGF). However, the pathways through which PD-MSCs exert protective effects on the ovary remain insufficiently defined. In this study, we examined whether PD-MSC transplantation ameliorates ovarian injury in a thioacetamide (TAA)-induced ovarian insufficiency model and explored the signaling events potentially associated with this response. Female rats were administered TAA for 12 weeks, and PD-MSCs were transplanted at week 8. We assessed ovarian morphology, fibrosis, oxidative stress markers, hormonal profiles, and follicle development. Complementary in vitro experiments using TAA-treated KGN granulosa-like cells were performed to investigate potential mechanistic associations. PD-MSC transplantation improved ovarian architecture, reduced collagen deposition, enhanced follicle growth, and mitigated oxidative stress. These changes were accompanied by increased PlGF expression and enhanced activation of fms-like tyrosine kinase-1 (Flt-1), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and nuclear factor erythroid 2-related factor 2 (Nrf2)-related antioxidant pathways. In vitro, PD-MSCs coculture similarly attenuated oxidative stress and partially improved mitochondrial membrane potential in damaged KGN cells. Together, these findings suggest that PD-MSCs ameliorate ovarian structural damage and oxidative stress in TAA-induced injury, potentially through paracrine mechanisms partly involving PlGF/Flt-1-associated antioxidant signaling. This work supports the therapeutic potential of PD-MSCs for metabolic or toxicant-induced ovarian insufficiency while underscoring the need for further studies to fully delineate the specific contribution of PlGF and its interaction with downstream antioxidant pathways. Full article

Background/Objectives: Thermal injuries represent a significant global health burden, often complicated by hypertrophic scarring, chronic inflammation, and delayed re-epithelialization. While Mesenchymal Stem Cell (MSC) transplantation has shown promise, its clinical translation is hindered by risks of tumorigenicity and immunological concerns. This study evaluates the efficacy of cell-free Extracellular Vesicle (EV) therapy—derived from both mammalian MSCs and plant sources (PDNVs)—as standardized, off-the-shelf alternatives. This study synthesizes evidence focusing on re-epithelialization velocity, angiogenic activity, and anti-fibrotic outcomes, while assessing the impact of second-generation delivery scaffolds on therapeutic durability. Methods: Conducted in accordance with PRISMA 2020 guidelines and registered in PROSPERO (CRD420261305379), this review interrogated PubMed, Scopus, Embase, and Web of Science for studies published between 2015 and 2026. Eligible studies included in vivo animal models of thermal injury using purified vesicles from mammalian MSC sources or plant-derived nanovesicles compared with placebo, standard care, or untreated controls. Data were synthesized narratively; methodological quality was appraised using the SYRCLE risk of bias tool and compliance with MISEV guidelines. Results: Synthesis of 50 studies revealed that vesicle-based interventions consistently accelerate wound closure and improve histological healing. Mammalian ADSC-derived vesicles demonstrated superior anti-fibrotic effects via the miR-192-5p and miR-125b-5p axes, while hUC-MSC vesicles attenuated systemic inflammatory signaling via miR-181c. Plant-derived nanovesicles (PDNVs) showed potent antioxidant and re-epithelialization effects, with emerging potential as engineered genetic carriers. Crucially, advanced delivery systems, including bioactive hydrogels and microneedle patches, were repeatedly associated with improved local retention and more durable effects than bolus injections. Conclusions: Vesicle-based therapies show consistent pro-healing signals in preclinical models, suggesting source-dependent profiles: MSC-derived vesicles excel in immunomodulation and anti-fibrotic remodeling, while PDNVs provide a scalable, low-immunogenicity platform. As a cell-free strategy, these therapies circumvent the safety risks of live cell transplantation. This review identifies a critical shift toward second-generation delivery scaffolds to overcome the clearance crisis of topical applications, emphasizing the need for harmonized MISEV-aligned characterization in future clinical translation. Full article

Human mesenchymal stem/stromal cells (MSCs) have attracted significant interest in regenerative medicine due to their self-renewal capacity, immunomodulatory functions, multipotency, and relative ease of isolation and expansion. However, several limitations restrict their clinical application, including cellular heterogeneity, challenges in large-scale expansion, and poor in vivo persistence after transplantation. Systemically administered MSCs are rapidly cleared because of limited adhesion, short survival time, and inefficient extravasation, resulting in suboptimal therapeutic efficacy. To overcome these challenges, various strategies have been developed, such as hypoxic preconditioning, biomaterial-based approaches, and genetic modification. Among these, genetic modification represents a particularly powerful and versatile strategy, as it enables targeted enhancement of specific functional properties of MSCs and even the introduction of novel therapeutic capabilities. In this review, we summarize recent advances in genetically engineered MSCs and categorize these approaches into four functional domains: migration, adhesion, secretion, and survival. We further discuss their therapeutic outcomes across diverse disease models in vivo. Collectively, genetic modification substantially enhances the intrinsic therapeutic potential of MSCs and represents a promising direction for the development of next-generation cell-based therapies. Full article

Heart failure (HF) has traditionally been regarded as a primary myocardial disorder in veterinary medicine. However, accumulating evidence suggests that HF represents a systemic syndrome characterized by dynamic multiorgan interactions. In human cardiovascular research, cardiorenal and cardiointestinal paradigms have reshaped disease conceptualization, yet comparable integrative frameworks remain underdeveloped in veterinary cardiology. Naturally occurring canine HF—particularly myxomatous mitral valve disease and dilated cardiomyopathy—offers a clinically relevant translational platform in which systemic remodeling unfolds within an intact physiological lifespan. This review proposes a systems-based perspective that integrates spontaneous canine HF with controlled in vivo experimental models. We outline four main pathways of interaction: (1) the heart–gut axis, wherein reduced perfusion can influence inflammation and disruption of the intestinal barrier; (2) the heart–bone axis, wherein endocrine factors like osteoprotegerin and osteocrin can impact remodeling of the cardiovascular system; (3) the heart–vascular endothelium axis, wherein inflammatory signaling and dysfunction of the vascular endothelium are hallmarks; and (4) the neurocardiac axis, which reflects an imbalance in the autonomic nervous system. Emerging regenerative and organelle-based strategies—including mesenchymal stem cell therapy and mitochondrial transplantation—are discussed within this multiorgan framework. Rather than focusing solely on cardiac contractility, these approaches may function as systemic inflammatory modulators, and endothelial, metabolic, and autonomic pathways. Canine HF can be better understood as a multiorgan network condition; reframing it in this way can help researchers in the field of translational cardiology create more comprehensive diagnostic and treatment plans. Full article

Diabetic retinopathy (DR) is a major cause of adult blindness and is characterized by progressive retinal vascular dysfunction and pathological angiogenesis. To establish a DR model, streptozotocin (STZ) was intraperitoneally injected into rats. After 8 weeks, naïve placenta-derived mesenchymal stem cells (PD-MSCs) or PEDF-overexpressing PD-MSCs (PD-MSCs^PEDF) were intravitreally transplanted into the right eye for 4 weeks. Pathological neovascularization in DR is regulated by the balance between vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). In diabetic retinas, increased VEGF and decreased PEDF expression were reversed following PD-MSC transplantation. Notably, PD-MSCs^PEDF treatment resulted in higher PEDF, and lower VEGF expression compared with naïve PD-MSCs, with similar expression patterns observed in the contralateral non-transplanted eyes. These findings indicate that engineering PD-MSCs^PEDF enhances anti-angiogenic activity by modulating VEGF and PEDF balance, thereby alleviating vascular damage in STZ-induced diabetic retinas. Full article