The S100A8/9 Fingerprint of Mesenchymal Stem Cells
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PROVIDER: PRJEB23139 | ENA |
REPOSITORIES: ENA
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Project description:Background: Non-healing wounds cause profound suffering of patients and a huge economic burden on society. Current research attempts to refine MSC-based therapies for this type of difficult-to-treat wounds. We earlier reported that injection of S100A8/A9 primed MSCs into the wound edge in mice accelerates wound healing compared to non-primed MSCs. We here describe a protective response of differentially expressed isoforms of genes, proteins and their potential role in the reported beneficial effects of S100A8/A9 primed MSCs on tissue repair. Methods: Adipose‐derived MSCs were characterized for specific cell surface markers using flow cytometry and assessed for their ability to differentiate into different lineages. To further investigate the mechanisms underlying the beneficial effects of S100A8/A9 primed MSCs, we employed a multi‐omics strategy that combined transcriptome, secretome, and proteome analyses. Global translational activity and a potential metabolic shift were examined using fluorescent labeling alongside seahorse‐based metabolic assays. Additionally, in silico analysis was conducted to assess the presence of the DRACH motif in mRNAs encoding these proteins, thereby evaluating their potential for cap-independent, m6A‐mediated translation. Results: Enhanced protein translation was observed in MSCs primed with S100A8/A9. Priming significantly increased the levels of the cap-independent translation initiation factor EIF3I, while reducing the cap-dependent factor EIF4A1, suggesting a shift in the mode of translation. In addition, the secretome of S100A8/A9-primed MSCs exhibited upregulation of cystatin C, a tissue protective protease inhibitor, and angiopoietin-1, an inducer of angiogenesis. Furthermore, various collagens, which serve as MSC niche-protecting proteins, were expressed at higher levels in the S100A8/A9 primed MSCs. Notably, the mRNAs corresponding to these factors contained DRACH motifs. Conclusion: We uncovered a protective response in S100A8/A9 primed MSCs that alters translation processes and increases the secretion of protective proteins, whose functions warrant further exploration. In the long term, S100A8/A9 priming holds promise for developing more effective MSC‐based therapies to enhance wound healing.
2026-06-09 | GSE301531 | GEO
Project description:Studies using bone marrow chimeric mice revealed that S100A8/A9 expression on myeloid cells is essential for development of colon tumors. Our results thus reveal a novel role for myeloid-derived S100A8/A9 in activating specific downstream genes associated with tumorigenesis and in promoting tumor growth and metastasis. Subconfluent cultures of MC38 cells were serum-starved for 16 hrs and activated with 10ug/mL S100A8/A9 for 6 hrs. Total RNA was extracted from unactivated or activated cells. 2 replicates each per stimulated cells, unstimulated cells, and control cells.
2011-02-01 | E-GEOD-26359 | biostudies-arrayexpress
Project description:In an inducible model of human breast cellular transformation, we map genome-wide chromatin binding of S100A8, S100A9 and Pol II. We show that the calcium-dependent cytokines S100A8 and S100A9 are recruited to numerous promoters and enhancers. This recruitment is associated with multiple DNA sequence motifs recognized by DNA-binding transcription factors that are linked to transcriptional activation and are important for transformation. Nuclear-specific expression of S100A8/A9 promotes oncogenic transcription and leads to enhanced breast transformation phenotype. These results suggest that, in addition to its classical cytokine function, S100A8/A9 can act as a transcriptional co-activator.
2021-01-01 | GSE155421 | GEO
Project description:S100A8/A9 plays a critical role in the formation of an immunosuppressive tumor microenvironment. Therefore, it is important to identify inhibitors targeting S100A8/A9 to enhance antitumor immunity. However, systemic targeting S100A8/A9 in clinical trials has shown minimal effects. Understanding the reasons underlying their underperformance is important for developing drugs targeting S100A8/A9 that could effectively reverse the immunosuppressive tumor microenvironment. In this study, using hematopoietic system-specific conditional knockout mice in heterotopic models of lung and colon cancer and systemic pharmacological interference, we demonstrated that S100A8/A9 perturbation in the hematopoietic system accelerates tumor progression by attenuating T cell-mediated antitumor immunity. Mechanistically, S100A8/9 perturbation triggered myeloid-biased differentiation in the bone marrow by promoting the production of abnormal granulocyte-monocyte progenitors. The local release of S100A8/A9 inhibitors using a tumor-targeted drug delivery system exhibited antitumor potential by avoiding myelopoiesis-promoting effects. These findings reveal a mechanism underlying the limited efficacy of systemic S100A8/A9 inhibition and propose a targeted strategy to enhance antitumor effects.
2025-07-14 | GSE300778 | GEO
Project description:Tumor-associated macrophages enhance the malignant phenotypes of esophageal squamous cell carcinoma (ESCC) cells. We have previously identified several factors associated with ESCC progression using an indirect co-culture assay between ESCC cells and macrophages. Here, we newly established a direct co-culture assay between ESCC cells and macrophages which is closer to the actual cancer microenvironment than an indirect co-culture assay. To investigate the gene expression changes by co-culture with macrophages, we performed cDNA microarray analysis between mono-cultured and co-cultured ESCC cells with macrophages. We found that the expression of S100 calcium binding protein A8 and A9 (S100A8 and S100A9) was enhanced in co-cultured ESCC cells with macrophages. S100A8 and S100A9 commonly exist stable and function as a heterodimer (S100A8/A9). S100A8/A9 is widely known as an inflammation marker. It also contributes to the enhancement of malignant phenotypes in several cancers. S100A8/A9 enhances the migration and invasion of ESCC cells by activating Akt and p38 MAPK signaling pathways. The higher expression levels of S100A8/A9 were associated with poor prognosis in ESCC patients. These results suggest that S100A8/A9 contributes to the progression of ESCC.
2021-12-01 | GSE174796 | GEO
Project description:Sjogren's syndrome (SS) dry eye is a chronic autoimmune eyedisease driven by T helper 17 (Th17)cells. S100A8/A9 has emerged as an important proinflammatory alarmin in variousautoimmune and inflammatory diseases. However, the role of S100A8/A9 in the pathogenesis of SS dry eye remains unexplored. Here,we show that the expression levels of S100A8/A9 were elevated in peripheral blood mononuclear cells (PBMCs) of patients with SS dry eye, as well as the lacrimal glands (LGs) of SS dry eye mice. The administration of paquinimod, a specific inhibitor of S100A8/A9, could alleviate the progression of SS dry eye with significant reduction of Th17 cell frequency in LGs, spleen and lymph nodes of SS dry eye mice.Further experiment revealed that S100A8/A9 did not directly affect Th17 generation and function, but upregulated the expression of MHCIl andI123a in DCs to augment Th17 cell response through a Acod1/STAT3-dependent signaling pathway in the context of SS dry eye. Together,these findings unveiled the key role of S100A8/A9 in the pathogenesis of SS dry eye and suggested a potential therapeutic avenue for SS dry eyeand otherTh7 cell-related autoimmune disorders.
2025-01-22 | GSE276800 | GEO
Project description:Studies using bone marrow chimeric mice revealed that S100A8/A9 expression on myeloid cells is essential for development of colon tumors. Our results thus reveal a novel role for myeloid-derived S100A8/A9 in activating specific downstream genes associated with tumorigenesis and in promoting tumor growth and metastasis.
2011-02-01 | GSE26359 | GEO
Project description:Sepsis-induced skeletal muscle atrophy is common in septic patients with the increases risk of mortality and is associated with myocellular mitochondrial dysfunction. Nevertheless, the specific mechanism of sepsis muscle atrophy remains unclear. Here we conducted a clinical retrospective analysis and observed the elevation of skeletal muscle index (ΔSMI) was an independent risk factor for 60-day mortality in septic patients. Moreover, in mouse model of sepsis, the skeletal muscle atrophy was also observed, which was associated with the upregulation of S100a8/a9-mediated mitochondrial dysfunction. Inhibition of S100a8/a9 significantly improved mitochondrial function and alleviated muscle atrophy. Conversely, administration of recombinant S100a8/a9 protein exacerbated mitochondrial energy exhaustion and myocyte atrophy. Mechanistically, S100a8/a9 binding to RAGE induced Drp1 phosphorylation and mitochondrial fragmentation, resulting in muscle atrophy. Additionally, RAGE ablation or administration of Drp1 inhibitor significantly reduced Drp1-mediated mitochondrial fission, improved mitochondrial morphology and function. Our findings indicated the pivotal role of S100a8/a9 in driving the mitochondrial fragmentation in septic muscle atrophy. Targeting S100a8/a9-RAGE-initiated mitochondrial fission might offer a promising therapeutic intervention against septic muscle atrophy. Taken together, our data provide a potential mechanism for sepsis-induced muscle atrophy.
2025-01-15 | GSE285318 | GEO
Project description:Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a monogenic autoinflammatory disease characterized by progressive arthritis with neutrophilic infiltration, cytopenia, and high serum S100A8/A9 and zinc. The molecular pathophysiology of PAMI caused by particular variants of the PSTPIP1 gene, such as PSTPIP1 E250K, is still unknown, and targeted therapy based on the pathogenesis has not been developed. We established an analytical model of neutrophils and monocytes/macrophages using induced pluripotent stem cells harboring the PAMI variant and another PSTPIP1 E250Q variant observed in PSTPIP1-related disorders with milder phenotypes. Using the model cells, we demonstrated increased production of reactive oxygen species, inflammatory cytokines, S100A8/9, increased cell death in the E250K neutrophils, and increased production of cytokines and abnormal phenotype of E250K monocytes/macrophages. With these model cells, we delved into the molecular basis of the hyperinflammation and pronounced S100A8/A9 production. Our data revealed that S100A8/A9 was at the center of hyperinflammation in PAMI syndrome and its deletion can reverse functional and molecular abnormalities in the phagocytes.
2026-06-25 | GSE270695 | GEO
Project description:Although the immune adapter protein ADAP (adhesion and degranulation protein adaptor protein) plays a critical role in regulating the inflammatory responses of macrophages, the impact of this regulation on intestinal inflammation remains elusive. This study reveals that mice with ADAP deficiency had an increased susceptibility to dextran sulfate sodium (DSS)-induced colitis. Furthermore, the absence of ADAP leads to increased expression of S100A8/A9 (also known as MRP8 and MRP14, respectively) both in vivo and in vitro, and increased susceptibility to intestinal inflammation. Mechanistically, we demonstrate that ADAP upregulates macrophage E3 ubiquitin ligase FBXW7 (F-box and WD repeat domain-containing 7), promoting proteasomal degradation of the transcription factor SPI1(SPI-1 proto-oncogene) and mediates this effect in macrophages during colitis. Whereas ADAP inhibits SPI1 expression in macrophages, ADAP deficiency promotes SPI1 expression and increases the binding of SPI1 to the S100A8/A9 promoter region. Blockade of SPI1 effectively prevents colitis-induced S100A8/A9 upregulation in macrophages. Thus, our findings highlight the potential link between ADAP and intestinal inflammation and pave the way for therapeutic interventions targeting the ADAP-SPI1-S100A8/A9 signaling axis in inflammatory colitis.
2026-01-28 | GSE303613 | GEO