Search Results (78)

Urine-derived stem cells (UDSCs) have emerged as a promising cell source for regenerative medicine due to their non-invasive procurement, high proliferative capacity, and potential relevance to kidney-specific repair. Unlike conventional mesenchymal stem cells (MSCs) obtained from bone marrow or adipose tissue, UDSCs originate from multiple regions of the urinary tract and exhibit a unique biological profile that combines MSC characteristics with features of renal progenitor populations. This review provides a comprehensive overview of the current understanding of UDSC biology, including their origin, isolation strategies, morphology, immunophenotypic characteristics, differentiation potential, and secretory profile. Particular attention is given to the expression of renal lineage-associated markers and pluripotency-related factors that may contribute to their regenerative capacity. The bioactive mediators of UDSCs regulate inflammation, oxidative stress, angiogenesis, and extracellular matrix remodeling, thereby influencing key pathways implicated in chronic kidney disease (CKD)-associated fibrosis. Furthermore, the intrinsic renal progenitor signature of UDSCs may provide advantages in renal homing and tissue-specific repair compared with conventional MSC populations. Despite encouraging preclinical findings, significant challenges remain, including cellular heterogeneity, inconsistent isolation efficiency, lack of standardized characterization criteria, and limited clinical validation. Collectively, current evidence positions UDSCs as a biologically distinct and therapeutically attractive platform for kidney regeneration. Full article

Background: Parvovirus B19 (B19V) has a well-established tropism for erythroid progenitor cells and is a recognized cause of anemia in immunocompromised individuals. Patients with end-stage renal disease (ESRD) receiving maintenance hemodialysis are predisposed to anemia due to multiple mechanisms and are frequently exposed to healthcare settings, raising concern that prior B19V infection may contribute to anemia severity or resistance to erythropoiesis-stimulating agents (ESAs). However, data regarding the clinical relevance of B19V seroprevalence in hemodialysis patients remain limited. Methods: We conducted a single-center, observational cross-sectional study including 131 adult patients on maintenance hemodialysis and 50 healthy controls. Parvovirus B19 IgG serostatus was assessed by enzyme-linked immunosorbent assay (ELISA) and used exclusively as a marker of prior (past) exposure rather than active infection; our aim was to determine whether IgG-defined prior exposure leaves a measurable long-term imprint on erythropoiesis. None of the participants had clinical features suggestive of acute parvovirus infection or an unexplained aplastic episode at enrollment. Demographic data, comorbidities, dialysis characteristics, ESA use, and laboratory parameters (hemoglobin, hematocrit, mean corpuscular volume, inflammatory markers, and albumin) were collected. Between-group and within-cohort comparisons used non-parametric tests, and multivariable logistic and linear regression models were used to adjust for age, sex, and other relevant covariates. Results: Parvovirus B19 IgG seropositivity was common in both groups (64.9% of hemodialysis patients vs. 48% of controls; crude odds ratio [OR] 2.00, 95% confidence interval [CI] 1.03–3.88, p = 0.043). However, hemodialysis patients were substantially older and more often male; after adjustment for age and sex, dialysis status was no longer independently associated with seropositivity (adjusted OR 1.4, 95% CI 0.8–2.3, p = 0.20), and within the hemodialysis cohort seropositivity was not associated with age or sex. Hemodialysis patients exhibited significantly lower hemoglobin and hematocrit and higher inflammatory markers than controls, consistent with ESRD-related anemia. Within the hemodialysis cohort, B19 IgG-positive and IgG-negative patients did not differ in hemoglobin, hematocrit, mean corpuscular volume, C-reactive protein, albumin, or ESA use, and IgG serostatus remained unrelated to hemoglobin in a multivariable model adjusting for age, sex, inflammation, nutrition, dialysis vintage, and ESA use (adjusted β = −0.20 g/dL, 95% CI −0.68 to 0.28, p = 0.42). Past Parvovirus B19 exposure was therefore not associated with anemia severity or treatment requirements. Conclusions: In this cohort of stable maintenance hemodialysis patients, prior Parvovirus B19 exposure, as indicated by IgG seropositivity, was not associated with increased anemia severity, inflammation, or ESA use, and the higher crude seroprevalence in dialysis patients was attributable to their older age rather than to dialysis itself. Because IgG reflects past exposure only and IgM and viral DNA were not assessed, these findings apply strictly to past (IgG-defined) exposure and cannot address active or persistent B19V infection. They suggest that routine Parvovirus B19 IgG screening in asymptomatic hemodialysis patients is unlikely to be useful for anemia management, whereas active or persistent infection—detectable only by molecular testing—remains the more plausible contributor to unexplained or refractory anemia and merits study in selected patients. Full article

Renal cell carcinoma (RCC) is acknowledged as a heterogeneous malignancy underlined by complex genetic, metabolic, and immune dysregulation. In particular, molecular studies have revealed distinct oncogenic mechanisms that have been exploited and studied as therapeutic intervention targets. These include hypoxia-driven signaling, chromosomal translocations, and gene fusion events that affect tumor progression. This review provides a comprehensive overview of these targets and rethinks RCC management. Therapeutic concepts include the targeting of genomic fusion biology with emerging cell-based immunotherapies or targeted molecular inhibition, and orthomolecular therapeutic strategies are presented. Two clinical and pathological features are highlighted—namely, the TFE3 fusion proteins in translocation RCC and the growing role of hypoxia-inducible factor-2α (HIF-2α) inhibitors in clear-cell RCC. We also present recent data on novel immunotherapeutic approaches, including autologous hematopoietic stem and progenitor cell-based interferon-α gene therapy, as well as chimeric antigen receptor T-cell therapy. These therapies are discussed in light of their mechanistic rationale, translational potential, and existing clinical challenges due to unwanted side effects. At last, orthomolecular and natural product-based therapies are reviewed for their potential as adjunctive therapies that might be used for oxidative stress management, the targeting of tumor metabolism and immune effects, and to increase standard treatment tolerance. This review points to a multidimensional framework that might support further research and studies in precision-guided RCC management, as integrative approaches may enhance therapeutic efficacy, reduce toxicity, and support the development of personalized interventions for advanced or treatment-resistant RCC. Full article

Mammals and reptiles possess a metanephric kidney as the terminal renal organ for homeostasis of solutes and waste products. The development of the metanephric kidney has primarily been studied in mammalian model systems. Little is known about the conservation of metanephric kidney formation in non-mammalian species such as reptiles. Uniquely, reptiles maintain kidney progenitor cell populations throughout life and continually develop new nephrons, the functional unit of the kidney. The red-eared slider turtle, Trachemys scripta elegans, was utilized to investigate the conservation of reptilian metanephric kidney development. The nephron progenitor cell (NPC) marker, Six2, was detected in whole-mount turtle kidneys in a similar pattern to mammals. However, there were differences in progenitor cell niche morphology where turtle NPC populations formed distinct elongated rows instead of the rosette-like morphology found in the mouse. The pattern of NPC populations in the embryonic turtle kidney was maintained in the adult turtle. Whole-genome bisulfite sequencing was performed on cortical tissue containing the NPC populations from adult turtle kidneys and compared to those of adult mice. Significant conservation of gene methylation was detected in adult cortical tissue between the two species, although unique signatures were detected in turtle samples related to DNA repair and β-catenin signaling. This suggests a high level of conservation of metanephric kidney development at the genetic level. Full article

Background/Objectives: Chronic lower limb ulcers represent a significant clinical challenge, with conventional therapies achieving healing in only 30–40% of complex cases. This study evaluated the comparative effectiveness of autologous blood clot therapy (ActiGraft, delivering platelet- and leukocyte-derived growth factors) and autologous micrograft therapy (Rigenera, containing viable progenitor cells) versus advanced wound dressings for refractory chronic wounds. Methods: This retrospective analysis of a prospectively collected, non-randomized clinical cohort included 132 patients with chronic lower limb ulcers refractory to prior therapy, who were treated between 2019 and 2024 at a single wound care center. The patients received ActiGraft (n = 32), Rigenera (n = 33), or advanced wound dressings (n = 67) based on their choice after informed discussion. The primary outcome was complete wound closure at 52 weeks. Multivariable Poisson regression with robust variance was performed, adjusting for baseline wound area (log-transformed), chronic renal failure, age, and peripheral vascular disease. Cox proportional hazards was used to model time to closure. Bonferroni correction (threshold p < 0.0167) was applied for three pairwise comparisons. This study was not pre-registered, and the results should be considered hypothesis-generating. Results: Unadjusted wound closure rates were 68.8% (ActiGraft; RR = 1.71, 95% CI: 1.17–2.48, p = 0.015), 60.6% (Rigenera; RR = 1.50, 95% CI: 1.01–2.25, p = 0.089), and 40.3% (advanced dressings). After multivariable adjustment, ActiGraft showed attenuated benefit (adjusted RR = 1.38, 95% CI: 0.86–2.21, p = 0.179), while the beneficial effect of Rigenera became non-significant (adjusted RR = 1.19, 95% CI: 0.73–1.94, p = 0.488). However, the adjusted Cox regression revealed significantly faster healing for ActiGraft (HR = 10.67, 95% CI: 4.17–27.30, p < 0.001) and Rigenera (HR = 4.12, 95% CI: 1.75–9.73, p = 0.001). Sensitivity analyses restricted to comparable wound sizes (≤10 cm²) showed a consistent direction of effect (ActiGraft 71.4% vs. Advanced 37.5%). Infection rates were lower in the autologous therapy groups (0–3.0% vs. 11.9%; Fisher’s exact p = 0.006). Conclusions: ActiGraft autologous blood clot therapy showed trends toward superior wound closure and demonstrated significantly faster healing compared to advanced dressings in patients with refractory chronic lower limb ulcers, with autologous micrograft therapy (Rigenera) showing intermediate results. Significant baseline imbalances in wound size limit causal inference from the closure rate comparisons. These hypothesis-generating findings from a non-randomized cohort warrant confirmation in adequately powered randomized controlled trials with stratification by wound characteristics. Full article

In this study, in a culture of renal epithelial cells, we identified those expressing nestin, a cytoskeletal protein associated with stem/progenitor/activated/proliferating cell states. A mouse expressing GFP under the nestin promoter was used, followed by cell isolation and culture. It is hypothesized that this can be used to assess the stem/progenitor/activated/proliferating cell level in a mixed kidney cell culture. Both nestin-positive and nestin-negative cells were demonstrated to be present in the culture. After visualization, cells were attached to a glass slide with a grid, fixed, and prepared for electron microscopy analysis, with each cell visually identified by light microscopy being analyzed. Electron microscopy revealed tight interactions between nestin-positive and nestin-negative cells. Significant differences in the ultrastructure of nestin-positive and nestin-negative cells were observed. Nestin-positive cells were distinguished by a high ribosome content, indicating high protein-synthesizing activity. In the nestin–GFP-high (sorted) population examined by electron microscopy, vesicle-containing protrusions were frequently observed. These cells could contain multiple nuclei of varying sizes and had a high content of lysosomes. No significant differences in mitochondrial ultrastructure were observed in nestin-positive and -negative cells, although functional characteristics evaluated by the membrane potential probe differed. Full article

Retinoic acid receptor (RARγ) mRNA is expressed spatially and temporally during mouse embryogenesis and largely within stem and progenitor cells, indicating a role in organ formation. RARγ agonism promoted the maintenance of hematopoietic stem cells, and blocked stem cell development as shown for hematopoiesis, zebrafish development, and chondrogenesis. Transgene expression enhanced the generation of induced pluripotent stem cells, indicating a role in ground-state pluripotency. RARγ is oncogenic in acute myeloid leukemia, cholangiocarcinoma, and colorectal, head and neck, hepatocellular, ovarian, pancreatic, prostate, and renal cancers. RARγ agonism or overexpression enhanced the proliferation of cancer cells. Conversely, antagonism or inhibition of all-trans retinoic acid synthesis led to the death of cancer cells including cancer stem cells. The pathways regulated by RARγ, via canonical activation and repression of gene expression, include Wnt/β-catenin and Notch signaling. RARγ also acts as a co-factor to Smad3 and reduced or enhanced TGFβ-driven and Smad3-mediated events when liganded and non-liganded, respectively. Collectively the findings support the view that RARγ plays a crucial role in controlling stem and progenitor cell behavior. Full article

Objectives: To investigate the characteristics of monoclonal human urine-derived stem cells (hUSCs) obtained through different culture protocols and compare their therapeutic effects on renal ischemia–reperfusion injury in mice. Methods: Monoclones of hUSCs derived from the urine of healthy volunteers were isolated and cultured using two different culture media. Flow cytometry, qRT-PCR and RNA sequencing were employed to characterize each monoclonal clone of multipotent stem cells across multiple passages. To evaluate their therapeutic effects on unilateral renal ischemia–reperfusion injury in BALB/c mice, 5 × 10⁵ hUSCs from each monoclonal clone were intravenously administered to mice via the tail vein, followed by assessments using Masson staining, qRT-PCR and renal tissue transcriptomics analysis. Results: Four monoclonal strains were successfully isolated from four fresh urine samples of a healthy young male volunteer: three cultured in EGM-MV medium and one in our modified medium. All four strains demonstrated stable expression of mesenchymal stem cell-related markers over eight passages of expansion. Bioinformatics analysis of multiple cell transcriptome datasets revealed that these four cell strains are more closely related to kidney tissue than to bone marrow mesenchymal stem cells (BMSCs), adipose-derived mesenchymal stem cells (ADMSCs), induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), and urothelial cells. Additionally, significant differences were observed in the expression of genes associated with kidney development among the four monoclonal strains. Furthermore, the therapeutic effects of different monoclonal clones on renal ischemia–reperfusion injury in mice showed notable variability. Conclusions: The isolated monoclonal urine-derived stem cells in this study were showed closer transcriptomic similarity to renal progenitor cells than to other mesenchymal stem cell types and possessed differential therapeutic effects on acute kidney injury. Full article

Chronic kidney disease (CKD) is a common and serious condition in felines. Accordingly, several cell therapies have been studied over the past decades for effective treatments. This study aimed to develop a new lineage of renal progenitor cells for use in cats with CKD. Metanephric and mesonephric progenitor cells were obtained from mesonephros and metanephros tissues of feline conceptuses at four distinct gestational stages. The cultured cells were characterized by their morphology, tumorigenic potential, immunophenotype determined by flow cytometry, and differentiation potential. We then conducted a pilot study in CKD-affected cats, comparing intraperitoneal injections of cultured metanephric progenitor cells (n = 4) to a placebo solution (n = 3). All four cell types exhibited adhesion and colony formation, but showed no tumorigenic potential. Cells tested positive for renal progenitor markers (CD117, Nephron, and WT1), confirming their identity. Treated cats showed no statistically significant differences (p ≤ 0.05) in any of the data analyzed. However, caregivers reported a voluntary increase in appetite after cell administration. Veterinarians confirmed this information during double-blind evaluations conducted after treatment. Although this data are qualitative, no clinical deterioration was observed in cats. Our results suggest that this new lineage of renal progenitor cells did not induce immediate adverse effects, thus supporting its potential for use in cell-based therapies. However, further studies are needed to evaluate its efficacy in treating renal diseases. Full article

Systemic sclerosis (SSc) is a heterogeneous disease characterized by vascular alterations, immune dysregulation, and fibrosis. Solid evidence supports the hypothesis that endothelial dysfunction is the key player in SSc vascular injury and a critical factor concurring to the initiation of SSc pathogenesis. This narrative review reports on persistent endothelial dysfunction, resulting from oxidative stress, autoimmunity, and impaired vascular repair, in the course of SSc, and how it can trigger and sustain fibrotic remodeling of various organs. In this paper, we also analyze the impact on SSc of impaired angiogenesis and vasculogenesis, diminished endothelial progenitor cell function, and endothelial-to-mesenchymal transition, which can collectively disrupt vascular homeostasis and promote myofibroblast activation. These pathologic events underlie the hallmark clinical manifestations, i.e., Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. The review highlights how recognizing SSc as a paradigm of systemic endothelial dysfunction may reframe our understanding of its physiopathology, modify current therapeutic strategies, and unveil new therapeutic targets. Full article

Studies on populations exposed to inorganic arsenic (iAs) have shown an association with the development of chronic kidney disease (CKD) and renal cell carcinoma (RCC). However, there are few studies addressing how acute exposure of the human kidney to iAs might lead to the long-term alterations that might lead to CKD or RCC. This laboratory’s hypothesis is that renal exposure to iAs might alter the renal cells responsible for the repair and regeneration of nephrons damaged by iAs exposure or other renal toxicants. The kidney possesses a minority epithelial cell population that co-expresses PROM1 and CD24, which are believed to be involved in renal epithelial cell repair. The purpose of this work is to understand the pathogenesis of CKD in renal cortical epithelial cells. Our model consists of acute and chronic exposure of i-As (III) to “Human Renal Tubular Precursor TERT” (HRTPT). The microarray and gene validation study demonstrated a sudden induction of microfibril associated protein 5 (MFAP5) and carcinoembryonic antigen related cell adhesion molecule 5 and 6 (CEACAM 5 and 6) in chronic i-As (III)-exposed cells. Chronically exposed cells also exhibited an induction of the pAKT/AKT pathway and SOX9 transcription factor. The targeting of MFAP5 and CEACAM 5/6 could, therefore, provide a potential therapeutic approach to CKD. Full article

Arsenic, in the form of inorganic arsenite, is toxic to the kidney and can cause acute kidney injury, manifesting as destruction of proximal tubule cells. Nephron repair is possible through the proliferation of resident tubular progenitor cells expressing CD133 and CD24 surface markers. We simulated regenerative repair in the continued presence of i-As (III) using a cell culture model of a renal progenitor cell line expressing CD133 (PROM1) and CD24. Continued exposure and subculturing of progenitor cells to i-As (III) led to a reduction in the expression of PROM1 and CD24, as well as a decrease in the ability to differentiate into tubule-like structures. Cessation of i-As (III) and recovery for up to three passages resulted in continued repression of PROM1 and reduced ability to differentiate. Chronically exposed cells exhibited an ability to form colonies in soft agar, suggesting neoplastic transformation. Chronically exposed cells also exhibited an induction of CD44, a cell surface marker commonly found in renal cell carcinoma, as well as in tubular repair in chronic renal injury such as chronic kidney disease. These results demonstrate potential adverse outcomes of renal progenitor cells chronically exposed to a nephrotoxicant, as well as in environmental exposure to arsenic. Full article

Background/Objectives: Multiple myeloma is a malignancy of plasma cells detected in the bone marrow, inducing symptoms like anemia, hypercalcemia, renal problems, and bone fractures in multiple myeloma patients, affecting their quality of life. The bone marrow microenvironment plays a crucial role in the prognosis and progression of the disease. The purpose of this study was to examine the relationship between the percentages of the major cell populations of the bone marrow, including immune cells, and physical function/quality of life in multiple myeloma patients after first-line treatment. Methods: Twenty-one multiple myeloma patients (N = 14 men, N = 7 women) participated in the study after completing first-line treatment. Bone marrow and blood samples were taken one hundred days after transplantation, while physical function (6 min walking test, handgrip test, maximal aerobic power, and isometric strength), health-related quality of life (QLQ-C30), and body composition (DXA) were assessed 2–5 days later. Flow cytometry was used to assess the percentages of plasma cells, mast cells, B cells (total, precursors, naïve, and memory), T cells (total, CD27− and CD27+), NK/NKT cells (total, CD27− and CD27+), eosinophils, monocytes, neutrophils, myeloid progenitors, erythroblasts, and erythroid progenitors, expressed as percentages of total nucleated cells of the bone marrow. Results: The percentage of CD27+ NK/NKT cells was correlated with five parameters of the quality of life questionnaire: physical function (r = 0.78, p = 0.005), role functioning (r = 0.69, p = 0.020), fatigue (r = −0.86, p = 0.000), pain (r = 0.68, p = 0.021), and dyspnea (r = −0.80, p = 0.003). Conclusions: In conclusion, stronger immune surveillance in the bone marrow from CD27+ NK/NKT cells is correlated with better quality of life in multiple myeloma patients. Full article

CD133+CD24+ renal tubular progenitor cells play a crucial role in the repair and regeneration of renal tubules after acute kidney injury. The aim of this study is to investigate the responses of the human renal tubular precursor TERT (HRTPT) CD133+CD24+ cells and human renal epithelial cell 24 TERT (HREC24T) CD133-CD24+ cells to hypoxic stress, as well as their gene expression profiles. Whole transcriptome sequencing and functional network analysis identified distinct molecular characteristics of HRTPT cells as they were enriched with hypoxia-inducible factor-1A (HIF1A), epidermal growth factor (EGF), and endothelin-1 (EDN1). Our in vitro experiments demonstrated that, under hypoxia (2.5% oxygen), HRTPT cells showed minimal cell death and a 100-fold increase in HIF1A protein levels. In contrast, HREC24T cells exhibited significant cell death and only a two-fold increase in HIF1A protein level. These results indicate that CD133+CD24+ renal tubular progenitor cells have enhanced survival mechanisms under hypoxic stress, enabling them to survive and proliferate to replace damaged tubular cells. This study provides novel insights into the protective role of CD133+CD24+ renal tubular progenitor cells in hypoxic renal injury and identifies their potential survival mechanisms. Full article

Cisplatin (CisPt) is a widely used chemotherapeutic agent. However, its nephrotoxic effects pose significant risks, particularly for the development of acute kidney injury (AKI) and potential progression to chronic kidney disease (CKD). The present study investigates the impact of non-lethal exposure of CisPt to immortalized human renal epithelial precursor TERT cells (HRTPT cells) that co-express PROM1 and CD24, markers characteristic of renal progenitor cells. Over eight serial passages, HRTPT cells were exposed to 1.5 µM CisPt, leading to an initial growth arrest, followed by a gradual recovery of proliferative capacity. Despite maintaining intracellular platinum (Pt) levels, the cells exhibited normal morphology by passage eight (P8), with elevated expression of renal stress and damage markers. However, the ability to form domes was not restored. RNA-seq analysis revealed 516 differentially expressed genes between CisPt-exposed and control cells, with significant correlations to cell cycle and adaptive processes, as determined by the Reactome, DAVID, and Panther analysis programs. The progenitor cells treated with CisPt displayed no identity, or close identity, with cells of the normal human nephron. Additionally, several upregulated genes in P8 cells were linked to cancer cell lines, suggesting a complex interaction between CisPt exposure and cellular repair mechanisms. In conclusion, our study demonstrates that renal progenitor cells can recover from CisPt exposure and regain proliferative potential in the continued presence of both extracellular CisPt and intracellular Pt. Full article