Stem Cells International最新文献

Background: The success of adipose stromal/stem cell (ASC)-based therapies may depend on donor characteristics such as body mass index (BMI). A high BMI may negatively impact the therapeutic potential of ASCs, but the effects of weight loss on ASC-mediated immunoregulation have not been extensively studied. Methods: ASCs were obtained from donors with obesity (obASCs) undergoing bariatric surgery and from the same donors after weight loss (wlASCs). Plasma samples, adipose tissue histology, and ASC characteristics, such as mitochondrial respiration and inflammatory factors, were studied before and after weight loss. The immunomodulatory capacity of ob/wlASCs was evaluated in cocultures with prepolarized and preactivated proinflammatory (M1) and anti-inflammatory (M2) macrophages by determining macrophage surface markers, gene expression, and cytokine secretion. Results: Weight loss significantly decreased plasma leptin levels and increased adiponectin levels. After weight loss, crown-like structures (CLSs) were undetectable, and the adipocyte size decreased. Weight loss significantly improved mitochondrial respiration in ASCs and resulted in a notable increase in their proliferative capacity. The proinflammatory marker genes tumor necrosis factor alpha (TNF-α), chemokine ligand 5 (CCL5), and cyclooxygenase-2 (COX2), as well as the proinflammatory cytokine interleukin 12p70 (IL-12p70), were significantly downregulated, while the anti-inflammatory gene tumor necrosis factor-inducible gene 6 (TSG6) was also significantly downregulated in ASC monocultures after weight loss. Following weight loss, ASCs exhibited increased proinflammatory properties when cocultured with macrophages, characterized by the downregulation of anti-inflammatory factors, along with the upregulation of several proinflammatory factors, compared with the effects of macrophage monocultures. Conversely, wlASCs demonstrated improved immunosuppressive functions in coculture with macrophages, as indicated by the upregulation of TSG6 gene expression and interleukin 4 (IL-4) secretion. Conclusions: Weight loss improved donors' metabolic health and partially recovered ASCs' anti-inflammatory gene expression and cytokine secretion profiles in monocultures. However, it was inadequate to fully restore the immunosuppressive functions of ASCs in cocultures with macrophages. Therefore, not only donor BMI but also weight loss history, among other donor characteristics, might be considered for optimal ASC-based therapy.

The development of enamel relies on the precise regulation of ameloblast differentiation, enamel matrix secretion, and mineralization. The formation of enamel is crucial for the normal function of dental tissues, and promoting enamel remineralization is of significant importance for the treatment of dental caries. Understanding the underlying mechanisms of enamel development is essential for oral therapy and provides a bridge to tooth regeneration. Among various growth factors, the insulin-like growth factor (IGF) family, including IGF-1 and IGF-2, has been shown to play a key role in enamel formation by activating signaling pathways such as PI3K/AKT and MAPK. This review summarizes the role of the IGF family in tooth development and enamel formation and sheds light on key parts of the research for future treatment improvements.

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.