Stem Cells International最新文献

Tendon tissue engineering draws on regenerative medicine principles, offering innovative solutions to address the challenges posed by tendon injuries and degenerative conditions. Tendons' inherent limited regenerative capacity often hinders complete recovery from injuries, leading to chronic conditions and impaired functionality. Autologous mesenchymal/stromal stem cells (MSCs) and tendon-derived stem cells (TSCs), combined with growth factors (GFs) like GDF-5, GDF-6 and GDF-7, are emerging as potential therapies for tendinopathy. These GFs are crucial for tendon development and promoting tenogenic differentiation, though the exact pathways they activate remain unclear. For this reason, directly comparing all three pathways to assess their impact on both MSCs and TSCs is essential. This study examined the effects of GDF-5, GDF-6 and GDF-7 on tenogenic differentiation in MSCs and TSCs, with a focus on how oxygen levels (21% O₂ vs. physoxia at 2% O₂) influence this process. The expression profiles of key tenogenic genes (Scleraxis [Scx], Tenomodulin [Tnmd], Thrombospondin-4 [Thromb-4] and Tenascin-C [Tnc-C]) were explored by quantitative reverse transcription PCR (RT-qPCR) following supplementation with individual GFs. Transcriptional analysis was complemented by Tnmd immunofluorescence (IF) and image analysis to identify optimal differentiation parameters. The study highlighted GDF-7 as a powerful inducer of tenocyte-like cell differentiation in MSCs, showcasing sustained expression of tenogenic genes over time in 21% O₂. Moreover, TSCs in physoxia differentiate into tenocytes without an additional GF requirement. In conclusion, the study lays a foundation for understanding the complex interplay of GFs, oxygen levels and cellular responses in the quest for tendon regeneration. In doing so, it establishes that different cell types have differing biochemical requirements for induction of tenogenic differentiation. While offering promising avenues for tissue engineering platforms, it underscores the need for further research to fully harness the potential of MSCs and TSCs in vivo for tendon regeneration.

Adipose-derived stem cells (ADSCs) demonstrated therapeutic potential in various fibrotic diseases, with their paracrine proteins playing a crucial role. Nonetheless, the principal paracrine factors of ADSCs responsible for antifibrosis have not yet been well identified. To address this issue, we initially confirmed that ADSCs could attenuate fibrosis and suppress TGF-β1 in bleomycin-induced skin fibrosis mouse models. RNA-sequencing of the cocultured fibroblasts demonstrated that ADSCs effectively inhibited the TGF-β/Smad2 signaling pathway in fibroblasts through the paracrine approach. Proteomic analysis of the cell supernatant (CS) demonstrated a significant upregulation of 97 proteins in the secretome of ADSCs, among which decorin (DCN) exhibited a particularly elevated level of overexpression. Protein-protein interaction (PPI) network analysis indicated a strong correlation between DCN and TGF-β1, with DCN effectively trapping TGF-β1 through core protein binding. Cell experiments demonstrated that DCN could effectively inhibit TGF-β1-induced fibroblast proliferation. Therefore, it was concluded that DCN was a crucial protein in ADSC secretome that exerted antifibrotic effects by inhibiting TGF-β1. This study conducted an in-depth insight into the paracrine function of ADSCs through transcriptome and proteome analysis, identifying DCN as an essential paracrine factor mediating the antifibrotic effect of ADSCs, which could provide valuable theoretical support for the use of ADSC secretions as well as DCN in the treatment of fibrotic diseases.

Dental stem cells are widely viewed as good options for bone regeneration because of their ease of acquisition, innate ability to renew themselves, and ability to differentiate into different types of cells. However, the process of osteogenic differentiation of dental stem cells is orchestrated by an intricate system of regulatory mechanisms. Recent studies have demonstrated the critical impacts of circular RNAs (circRNAs) on osteogenic differentiation of dental stem cells. Exploring the roles and regulatory pathways of circRNAs in dental stem cells could identify novel targets and approaches for utilizing dental stem cell therapy in clinical settings. This review provides a comprehensive overview of the functions and mechanisms of circRNAs, with a particular focus on their expression patterns and regulatory roles in osteogenic differentiation of various dental stem cell types. Furthermore, this review discusses current research challenges in this field and proposes future directions for advancing our understanding of circRNA-mediated regulation in dental stem cell biology.

Mounting evidence indicates that exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-exosomes) combine the advantages of hucMSC pluripotency with their nanoscale dimensions, enhancing their clinical potential through prolonged circulation half-life. Despite these promising characteristics, research on their immunological toxicity remains insufficient. This study focuses on the impact of hucMSC-exosomes on the general toxicity and immunopathological indicators. When mice received tail vein injections of 6 × 10¹⁰ hucMSC-exosomes particles, we observed no significant changes in body weight, feed intake, blood composition, organ indices, or histopathological findings throughout the 14 days observation period. Similarly, blood levels of immunoglobulins, cytokines, and lymphocyte subpopulations remained stable. The hucMSC-exosomes produced no detectable negative effects on immune organs including the thymus, spleen, and bone marrow. These findings indicate that intravenous administration of 6 × 10¹⁰ particles of hucMSC-exosomes appears relatively safe at the murine level. This assessment of safety and immunological impact following intravenous hucMSC-exosomes infusion offers experimental support for potential clinical applications and future analyses in this field.

Spermatogonial stem cells (SSCs) are essential for the initiation and continuation of spermatogenesis, a process fundamental to male fertility. Despite extensive studies on mouse SSCs, the mechanisms governing self-renewal and differentiation in human SSCs remain to be elucidated. This study investigated the regulatory mechanisms of SSCs by analyzing single-cell sequencing data from the GEO dataset of human testis. Analysis revealed dominant expression of CITED2 in human SSCs. Reduction of CITED2 levels in hSSC lines significantly inhibited proliferation and increased apoptosis. Protein interaction prediction and immunoprecipitation identified interactions between CITED2 and EP300 in SSC lines. RNA sequencing results indicated that CITED2 knockdown significantly affected the MAPK pathway and the HSPA6 gene. Overexpression of HSPA6 mitigated the proliferative and apoptotic changes provoked by CITED2 downregulation. These findings provide novel insights into the regulatory and functional mechanisms of CITED2-mediated hSSC development.

Olfactory dysfunction is one of the most prevalent diseases in otorhinolaryngology, particularly since the coronavirus 2019 (COVID-19) pandemic, with a potential impact on daily life. Several etiological factors can contribute to olfactory dysfunction owing to the complexity and specificity of the olfactory transmission pathway. However, current treatments for olfactory dysfunction are limited and their efficacy is unsatisfactory. Olfactory stem cells are multifunctional stem cells in the olfactory mucosa that comprise both horizontal and global basal stem cells (HBCs and GBCs, respectively). These cells can differentiate into various cell types in response to different stimuli with distinct characteristics. The aim of the study was to discuss the mechanisms and functions of stem cells and their application in the treatment of olfactory dysfunction.

A highly reproducible and functional liver model that closely resembles the human liver plays a crucial role in drug development, disease research, personalized medicine, and regenerative medicine. This study aimed to establish an in vitro liver model using skin epidermal progenitor cells (EPCs), which are easily accessible and exhibit a high proliferative capacity. Skin EPCs with high integrin beta 1 expression demonstrated multipotent differentiation potential, capable of differentiating into adipocyte- and neuron-like cells in vitro. Furthermore, when exposed to high concentrations of activin A, along with Wnt3a and BMP4, these cells efficiently differentiated into definitive endoderm, exhibiting high FOXA2 expression. Under our culture conditions, they further differentiated into functional hepatocytes. These differentiated cells exhibited high albumin secretion, CYP activity, and drug metabolism capabilities similar to those observed in vivo. In conclusion, this study highlights the potential of EPCs to differentiate into functional hepatocytes, providing a feasible and scalable source of hepatocytes for drug screening, liver disease modeling, and potential cell-based therapies.

Autoimmune diseases (AIDs) occur when the immune system mistakenly attacks the body's own antigens. Traditionally, these conditions are treated with nonspecific immunosuppressive therapies, including corticosteroids, immunosuppressants, biological agents, and human immunoglobulins. However, these treatments often fail to achieve optimal outcomes, especially for patients with severe cases. Mesenchymal stem cells (MSCs) present a promising alternative due to their robust self-renewal capabilities and multidirectional differentiation potential. MSCs are easily accessible, exhibit low immunogenicity, and can help reduce graft rejection. MSCs can inhibit T cell proliferation, reduce proinflammatory T cells, inhibit B cell differentiation, induce macrophage polarization towards the anti-inflammatory M2 phenotype, and suppress activity of natural killer (NK) cells and dendritic cells (DCs). Additionally, MSCs can regulate T cells, macrophages, and fibroblast-like synoviocytes (FLS) by releasing microRNA (miRNA) through exosomes or extracellular vesicles (EVs), thus providing therapeutic benefits for various diseases. Numerous clinical trials have highlighted the therapeutic benefits of MSCs in treating various AIDs, leading to increased interest in MSC transplantation. This review summarizes the current applications and mechanisms of action of MSCs in the treatment of AIDs.

Objectives: The goal of this study was to examine the existing evidence from randomized controlled trials (RCTs) on the efficacy of cell treatment in alveolar cleft (AC). Design: An electronic search was done for studies published between January 2000 and May 2024 in the PubMed/MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases. Primary outcomes were the radiographic assessment of bone graft volume, and the secondary outcome of interest was the number of complications after surgery. A random-effects model and fix-effect model were employed to pool effect sizes, and heterogeneity was assessed using I ² statistics. Results: Four RCTs, comprising 51 patients, were included in the systematic review and meta-analysis. No statistically significant difference in bone volume (MD [mean difference] -0.82; 95% CI [-3.59, 5.24]; p=0.71) when using cells therapy to repair AC compared to using autologous iliac crest bone graft repair AC. Also, there is no difference in postoperative complications (MD 0.66; 95% CI [0.13, 3.39]; p=0.62) between the two groups. In this meta-analysis, cells therapy on alveolar bone grafting produced results comparable to autologous bone grafting in new bone formation rate and complications. Conclusions: In conclusion, this systematic review and meta-analysis appear to indicate no disadvantage to utilizing cell therapy in AC reconstruction versus autologous bone grafting in terms of bone volume or complications.

Background: Ovarian cancer (OC) stands as the leading cause of cancer-related deaths among women, globally, owing to metastasis and acquired chemoresistance. Cancer stem cells (CSCs) are accountable for tumor initiation and exhibit resistance to chemotherapy and radiotherapy. Identifying stemness-related biomarkers that can aid in the stratification of risk and the response to chemotherapy for OC is feasible and critical. Methods: Gene expression and clinical data of patients with OC were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. Four thousand three hundred seventeen stemness-related genes (SRGs) were acquired from the StemChecker database. TCGA was used as the training dataset, while GSE30161 served as validation dataset. Univariate Cox regression analysis was used to identify overall survival (OS)-related SRGs, and multivariate Cox regression analysis and random survival forest analysis were used for generating stemness-relevant prognostic model. Kaplan-Meier plots were used to visualize survival functions. Receiver operating characteristic (ROC) curves were used to assess the prognostic predictive ability of SRG-based features. Associations between signature score, tumor immune phenotype, and response to chemotherapy were analyzed via TIMER 2.0 and oncoPredict R package, respectively. A cohort of Shanghai Cancer Center was employed to verify the predictive robustness of the signature with respect to chemotherapy response. Results: Seven SRGs (actin-binding Rho activating C-terminal like (ABRACL), growth factor receptor bound protein 7 (GRB7), Lin-28 homolog B (LIN28B), lipolysis stimulated lipoprotein receptor (LSR), neuromedin U (NMU), Solute Carrier Family 4 Member 11 (SLC4A11), and thymocyte selection associated family member 2 (THEMIS2)) were found to have excellent predictive potential for patient survival. Patients in the high stemness risk group presented a poorer prognosis (p  < 0.0001), and patients with lower stemness scores were more likely to benefit from chemotherapy. Several tumorigenesis pathways, such as mitotic spindle and glycolysis, were enriched in the high stemness risk group. Tumor with high-risk scores tended to be in a status of relatively high tumor infiltration of CD4+ T cells, neutrophils, and macrophages, while tumor with low-risk scores tended to be in a status of relatively high tumor infiltration of CD8+ T cells. Conclusions: The stemness-relevant prognostic gene signature has the potential to serve as a clinically helpful biomarker for guiding the management of OC patients.