Stem Cells International最新文献

Osteoarthritis (OA) represents a significant challenge in both orthopedic research and clinical practice, necessitating the development of effective therapeutic strategies. Here, we describe an ex vivo model based on osteochondral (OCh) explants housed in a three-dimensional printed device that enables the separation of bone and cartilage compartments. Our model demonstrates effective partitioning, as confirmed by significant differences in measurements of tissue-specific markers. The markers included matrix metalloproteinase (MMP) activity and sulfated glycosaminoglycan (sGAG) release for cartilage and alkaline phosphatase (ALP) activity, tartrate-resistant acid phosphatase (TRAP) activity, and osteocalcin (OC) levels for bone. The cartilage compartment of OCh explants was exposed to inflammatory stimuli, to mimic the OA-related microenvironment, using 10 ng/mL TNFα and 1 ng/mL IL-1β. Cytokine administration was coupled with secretome (or conditioned medium, CM) treatment obtained from 5 × 10⁵ naïve or cytokine-primed adipose-derived mesenchymal cells (CM and pCM). After 3 days, inflammatory cytokines induced a significant upregulation of MMP activity, effectively countered by both CM and pCM, alongside a modest increase in sGAG release. No major changes were detected in the bone counterpart. This study holds dual significance: firstly, the development and preliminary assessment of a human-based ex vivo model in accordance with 3Rs (Replacement, Reduction, Refinement) principles in preclinical research; secondarily, the evidence of an anti-catabolic potential of the adipose-derived mesenchymal cell secretome contributes, within a broader research context, to hypothesizing its potentiality in counteracting OA-associated hallmarks, with possible applications at early onset to mitigate the degenerative processes of this pathology. Trial Registration: ClinicalTrials.gov identifier: NCT04223622.

Purpose: This research attempts to assess the prognostic significance of serum/glucocorticoid-regulated kinase 1 (SGK1) expression in peripheral blood mononuclear cells (PBMCs) of multiple myeloma (MM) individuals undergoing autologous hematopoietic stem cell transplantation (AHSCT) compared to traditional minimal residual disease (MRD) and serum free light chain (sFLC) assessments.

Methods: A single-center, retrospective study was carried out involving 85 MM individuals who underwent AHSCT. SGK1 gene expression was measured in PBMCs using quantitative real-time PCR (qRT-PCR) at baseline and at defined post-transplant intervals. Concurrently, MRD status was assessed using multiparameter flow cytometry (MFC) and sFLC levels were measured. Individuals were seen for a median of 36 months post-transplant. ROC curve analysis was employed to assess the predictive power of SGK1 expression, MRD, and sFLC for relapse.

Results: SGK1 gene expression demonstrated dynamic changes in AHSCT, with levels decreasing in all risk groups, reflecting reductions in disease burden. Quantitative analysis showed that the predictive efficacy of SGK1, utilizing the area under the receiver operating characteristic (ROC) curve (area under the curve [AUC]), was highly comparable to that of MRD assessments, with SGK1 achieving an AUC of 0.86, closely approximating the MRD AUC of 0.88. Persistent high SGK1 expression, particularly discernible in individuals harboring high-risk (HR) cytogenetic profiles, was considerably associated with an elevated risk of relapse (hazard ratio for high vs. low SGK1 expression: 2.7; 95% CI: 1.4-5.3; p  < 0.01).

Conclusion: SGK1 gene expression in PBMCs serves as a promising, minimally invasive biomarker for relapse prediction in MM individuals undergoing AHSCT.

Objective: Diabetic ulcers are serious chronic wounds that are challenging to heal and can lead to amputation or even death. This study aims to utilize interleukin-10 (IL-10) overexpressing adipose mesenchymal stem cells to investigate their potential in promoting the healing of diabetic ulcers and to explore their mechanism of action.

Methods: The analysis of stem cell characteristics of ADSC-IL10 was performed through flow cytometry, cell scratch assay, MTT assay, and adipogenic and osteogenic differentiation assays. The detection of the M1 and M2 phenotypes of mouse peritoneal macrophages (RAW 264.7) under conditioned medium stimulation was carried out using qPCR technology. The assessment of the effects of conditioned media from ADSCs overexpressing IL-10 (ADSC-IL10 CM) and conditioned media from adipose-derived stem cells (ADSC CM) on the migration of normal skin fibroblasts and human immortalized epidermal cells was done using Transwell and cell scratch methods. A diabetic mouse model was induced using a high-fat/high-sugar diet plus streptozotocin (STZ) to detect the number of M2 macrophages and the expression levels of inflammatory factors (IL-1β, IL-6, IL-10, and MCP-1) and growth factors (EGF, VEGF, and TGFβ-1) in mouse skin tissue.

Results: The overexpression of IL-10 did not change the biological properties of ADSCs. In diabetic mice, the transplantation of IL-10 overexpressing ADSCs for wound healing was more effective than the transplantation of ADSCs alone. ADSCs overexpressing IL-10 promoted the expression of M2 macrophages marker; inhibited the secretion of proinflammatory factors such as IL-1β, IL-6, and MCP-1; and enhanced the production of growth factors including EGF, TGFβ-1, and VEGF. Furthermore, it facilitated the migration of skin fibroblasts and epidermal cells from diabetic mice to the wound site.

Conclusion: ADSCs that overexpress IL-10 promote wound healing in diabetic mice by reducing inflammatory responses, enhancing growth factor secretion, and increasing the migration of fibroblasts and epidermal cells.

Epilepsy affects over 70 million individuals globally, with nearly one-third of patients failing to achieve seizure control despite the continued availability of new technologies and medications. Current epilepsy research aims to prevent or arrest the onset and progression of epilepsy by seeking novel therapeutic targets and developing potent medications. Neuroinflammatory pathways may underlie the core pathophysiology of epileptogenesis, according to evidence from clinical and fundamental research. Intervening in neuroinflammatory pathways can delay the onset and progression of epilepsy. Mesenchymal stem cells (MSCs) have recently garnered notable attention for their robust immunomodulatory and anti-inflammatory properties in the context of inflammatory and immune-mediated diseases, suggesting their potential as promising candidates in epilepsy management. The therapeutic efficacy of MSCs is largely ascribed to their paracrine function, particularly exosomes, as confirmed by numerous pertinent studies. This review synthesizes preclinical and clinical studies of MSCs and their exosomes in epilepsy treatment, elucidating their mechanisms of action. Collectively, these studies indicate that MSCs and their exosomes have the potential to serve as innovative epilepsy treatment in the future. Trial Registration: ClinicalTrials.gov identifier: NCT05886205.

[This retracts the article DOI: 10.1155/2015/632305.].

Background: Oxidative stress plays a crucial role in the pathogenesis of periodontitis and compromises the regenerative potential of human periodontal ligament stem cells (hPDLSCs). Astaxanthin (ASX), a potent natural antioxidant with both lipophilic and hydrophilic properties, has been shown to scavenge reactive oxygen species (ROS). However, its protective effects on hPDLSCs under oxidative stress remain largely unexplored.

Methods: hPDLSCs were isolated and characterized. An oxidative stress model was established by exposing cells to 300 μM H₂O₂ for 6 h, followed by treatment with 10 μM ASX. Cellular viability, cytoskeletal integrity, ROS accumulation, inflammatory cytokine expression, osteogenic differentiation, and activation of the Nrf2/ARE pathway were assessed.

Results: ASX significantly reduced intracellular and mitochondrial ROS levels, preserved mitochondrial membrane potential, and inhibited H₂O₂-induced expression of TNF-α, IL-1β, IL-6, and MCP-1. Moreover, ASX promoted osteogenic differentiation, as evidenced by enhanced alkaline phosphatase (ALP) activity, increased mineralized nodule formation, and upregulation of RUNX2, OCN, and COL1. Mechanistically, ASX activated the Nrf2/ARE pathway, leading to increased expression of Nrf2 and its downstream antioxidant enzymes (HO-1, NQO-1, and GCLC).

Conclusion: These findings demonstrate that ASX ameliorates oxidative stress-induced injury in hPDLSCs via the Nrf2/ARE signaling pathway, exerting antioxidative, anti-inflammatory, and pro-osteogenic effects. This suggests its therapeutic potential for promoting periodontal regeneration under oxidative microenvironments.

Bone marrow mesenchymal stromal cells (BMSCs) have been shown to enhance the function of pancreatic beta-cells under hypoxic conditions. However, the precise mechanisms underlying this protective effect remain elusive. In this study, we established a hypoxic beta-cell model using murine pancreatic beta-TC-6 cells to investigate the protective effect and mechanism of BMSCs and their secreted extracellular vesicles (BMSC-EVs) on hypoxic β cells. Our findings reveal that coculture with BMSCs or BMSC-EVs significantly enhances the viability and survival of hypoxic beta-TC-6 cells. Molecularly, hypoxic conditions trigger an upregulation of CD36 in beta-TC-6 cells, a response that is counteracted by BMSCs or BMSC-EVs. Through a screening process for microRNAs (miRNAs) capable of degrading CD36 mRNA, we identified miR-539-3p as a potent suppressor of CD36 expression. The miR-539-3p mimic was found to bolster the viability of hypoxic beta-TC-6 cells, concurrently reducing CD36 mRNA levels by targeting its 3' untranslated region (3'UTR). In contrast, the miR-539-3p inhibitor abrogates the protective effects of BMSCs and BMSC-EVs on these cells. Additionally, knockdown of CD36 in hypoxic beta-TC-6 cells restores the protective function mitigated by miR-539-3p inhibition. In aggregate, these results suggest that BMSCs and BMSC-EVs shield beta-TC-6 cells from hypoxia-induced injury through miR-539-3p-mediated downregulation of CD36, underscoring the therapeutic potential of targeting the miR-539-3p-CD36 axis to enhance pancreatic beta-cell function in diabetic patients.

Background: Mesenchymal stem cells (MSCs) have shown promise in preclinical models for enhancing bone regeneration around dental implants. However, clinical evidence regarding their efficacy in maxillary sinus augmentation procedures for dental implants remains inconclusive.

Objective: To evaluate the clinical effectiveness of MSC-based regenerative therapies compared to conventional grafting in maxillary sinus augmentation for implant placement.

Methods: A systematic review and meta-analysis were conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and registered in PROSPERO (CRD42023488758). Electronic and gray literature searches were performed across six databases. Eligible studies included randomized clinical trials evaluating MSC-based bone regeneration in maxillary sinus lifts. Risk of bias (RoB) was assessed using the Cochrane RoB 2.0 tool, and certainty of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Meta-analyses were performed for implant success rate and bone formation outcomes.

Results: Six randomized controlled trials (RCTs) were included, comprising 74 patients and 222 implants. Meta-analysis revealed no statistically significant difference in implant success rate between MSC and control groups (risk ratio [RR] = 0.98; 95% confidence interval [CI]: 0.94-1.03; p = 0.50; I ² = 11.69%). For bone neoformation, continuous data favored the control group (standardized mean difference [SMD] = -0.83; 95% CI: -1.37 to -0.30; p = 0.002; I ² = 0%; indicating a medium to large effect size that represents a clinically perceptible advantage in bone formation for the control interventions), while dichotomous outcomes showed no significant difference (RR = 1.11; 95% CI: 0.73-1.67; p = 0.62). Sensitivity analyses confirmed the robustness of findings. The certainty of evidence was rated as high for bone formation outcomes and moderate for implant success.

Conclusions: MSC-based regenerative therapies do not appear to offer a significant clinical advantage over conventional grafting techniques in maxillary sinus augmentation. These results should be interpreted with caution, given the limited number of trials and clinical heterogeneity. Further well-designed studies are needed to validate their efficacy in implant-related bone regeneration.

Recurrent pregnancy loss (RPL), defined as more than two consecutive miscarriages before 20 weeks of gestation, affects 1%-5% of reproductive-aged women, with nearly half of the cases remaining idiopathic. Using ethanol-induced endometrial injury in rats to simulate RPL, we demonstrated that mesenchymal stem cells (MSCs) exert therapeutic effects through two complementary mechanisms: CCR7-mediated endometrial repair and immunomodulation of uterine natural killer (uNK) cells, compared to ethanol-induced injury, this treatment achieved a 190% increase in embryo retention (from 2.4 to 7 embryos). Transcriptomic analysis and Western blotting of MSC-cocultured NK92 cells revealed significant CCR7 upregulation (1.75-fold increase at the optimal dose of 2 × 10⁴ cells/mL MSCs) and activation of NK differentiation pathways. This was corroborated by immunofluorescence showing enhanced CCR7⁺ NK cell infiltration in MSC-treated endometria. MSCs administration altered cytokine profiles by decreasing pro-inflammatory mediators (IL-6, TNF-α, and IL-1β) and increasing anti-inflammatory IL-10 levels simultaneously. Mechanistically, MSCs orchestrate endometrial repair through sequential events: induce the formation of a gradient of CCR7 expression on the endometrial layer and the surface of NK cells; followed by ERK/JNK pathway activation, which promotes CCR7⁺ uNK cell generation; and finally initiates endometrial proliferation with an increased proportion of Ki67⁺ cells. Our integrated multi-omics approach-combining RNA-Seq, protein analysis, and cytokine profiling-establishes the CCR7-ERK/JNK axis as a promising therapeutic target, providing clinically relevant parameters for MSCs dosing and administration protocols in idiopathic RPL management.

Recently, we used kinetic stem cell (KSC) counting to show that the stability of the stem cell fraction (SCF) during serial culture expansion of human oral alveolar bone mesenchymal tissue cell (MTC) preparations varied significantly among patient donors. Whereas some patient donor samples' SCFs declined rapidly, others showed a moderate decrease; and still others had highly stable SCFs during serial culture expansion. Defining the cell kinetics basis for these differences in SCF stability could lead to effective solutions for the problem of loss of mesenchymal stem cell (MSC) function when MTC preparations are expanded for research and clinical applications. Using KSC counting, we show that greater SCF stability is associated with smaller stem cell turnover units, which reduce the SCF by cell dilution. This finding confirms earlier evidence and proposals that, by limiting the production and proliferation of committed progenitor cells, more effective expansion of tissue stem cells, such as MSCs, can be achieved. Because of the universal nature of tissue stem cell turnover units and the continuation of their basic cell kinetics programs in in vitro cell culture, the effects defined herein are predicted to apply to other types of human tissue stem cells of interest for stem cell medicine.