Biology subjects

Nakchbandi, I. A.

Publications and source records attributed to Nakchbandi, I. A..

3 recordsLinked to original sources

bioRxiv2025

THE IMMUNE RESPONSE AGAINST CANCER IS MODULATED BY STROMAL CELL FIBRONECTIN

Cancer-associated fibroblasts remain poorly understood, with some of them originating from the bone marrow. We therefore took advantage of the diversity of bone marrow stromal cells to shed light on how fibroblasts modulate cancer growth. In two murine cancer models, adding these fibroblasts to tumor cells resulted in smaller lesions. Suppression was enhanced by pretreatment with fibronectin, while genetic deletion of fibronectin in a small subpopulation of stromal cells expressing osterix/sp7 restored growth. The suppressive stromal population showed two more characteristics: the absence of CD31/pecam1 and CD105/endoglin. However, only a decrease in CD105/ENDOGLIN in melanoma patients translated in improved survival. Mechanistically, fibronectin or fibronectin fragments activate integrin 5{beta}1 and TLR4 and increase chemokine production by stromal cells ultimately leading to enhanced recruitment and activity of Ly6G+ myeloid cells without T-cell involvement. This work thus characterizes a beneficial interaction between stromal cells and neutrophils enhancing the immune response against early cancer. HighlightsO_LIStromal cells can be divided into two populations, a tumor supportive one with the potential to stimulate angiogenesis and an inhibitory one with the potential to enhance the immune response C_LIO_LIStromal fibronectin expressing the transduction factor osterix/sp7 produce fibronectin that acts on 5{beta}1 integrin and/or TLR4 on neighboring fibroblasts to modulate Ly6G+ immune cells and suppress tumor growth C_LI One sentence summaryTumor inhibitory fibroblasts have three characteristics and through production of fibronectin act on neighboring cells inducing signaling cascades that ultimately lead to a stronger immune response against early cancer.

cancer biology↗

bioRxiv2025

Modulation of collagen-binding integrins affects fibroblast activation and inhibits fibrosis

The extracellular matrix contributes to the progression of several diseases, sometimes by disrupting organ function such as in lung and liver fibrosis. Because integrin receptors mediate cell-matrix interactions, we conditionally deleted {beta}1 integrin in murine hepatocytes in vivo. Increased TGF-{beta} and matrix deposition ensued. Application of a cyclic peptide (GLQGE) that binds to both 10{beta}1 and 11{beta}1 diminished fibrosis in two murine models. In liver fibrosis, TGF-{beta} production was reduced. In lung fibrosis, however, the effect was exclusively due to suppressing fibroblast activation and hence collagen production without TGF-{beta} involvement. In summary, integrin manipulation successfully changed cell behavior, with effects differing depending on the cell type. Importantly, it is possible to directly suppress fibroblast activation and consequently diminish matrix production independent of disease pathogenesis. This underscores the importance of matrix composition in modifying the behavior of embedded cells and hence disease severity. Key findingsO_LILoss of 11{beta}1 integrin-mediated signal in hepatocytes increases TGF-{beta} and leads to fibrosis C_LIO_LIEngaging 10{beta}1 and/or 11{beta}1 with a cyclic peptide (GLQGE) inhibits fibroblast activation directly and, consequently matrix production and progression of fibrosis C_LI

cell biology↗

bioRxiv2025

EVALUATION OF STAINING FOR FIBRONECTIN ISOFORMS IN LIVER DISEASES

Fibronectin is an ubiquitous extracellular matrix protein, that is produced by the hepatocytes contributing to circulating fibronectin, and by the hepatic stellate cells contributing to fibrotic bundles. Fibronectin is required for the accumulation of collagen type I, the main fibrotic collagen in liver disease. It is presumed that cellular fibronectins including EDA-containing, EDB-containing and oncofetal fibronectin are the ones localized to the fibrotic bundles, since these isoforms are increased in the presence of fibrosis and cirrhosis in patients with liver disease. The aim of this work was therefore to evaluate the distribution of the various isoforms and determine whether they are detected in the hepatocytes too or whether they are indeed limited in their expression to fibrotic bundles. Total fibronectin was detected in hepatocytes particularly in healthy liver tissue. In advanced disease, fibronectin staining seemed diminished. All three isoforms, EDA-, EDB-, and oFN were detected in hepatocytes or the fibrotic bundles, with EDB being the most abundant. Interestingly, the isoforms did not fully account for all of fibronectin. Staining patterns confirmed that the three isoforms are not limited to the fibrotic bundles, but are also found in the hepatocytes. This contradicts the common notion that cellular fibronectins precipitate and are localized in the matrix, and explains why they can be measured in the circulation. Finally, there is some convergence between the presence of the isoforms in the fibrotic bundles and the elevation of their levels in the blood stream at least in chronic hepatitis C and cholestatic liver disease. This is in line with a high degree of complexity of fibronectin distribution and effects.

cell biology↗