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Background: In malignant melanoma, liver metastases significantly reduce survival, even despite highly effective new therapies. Given the increase in metabolic liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), this study investigated the impact of liver sinusoidal endothelial cell (LSEC)-specific alterations in MASLD/MASH on hepatic melanoma metastasis. Methods: Mice were fed a choline-deficient L-amino acid-defined (CDAA) diet for ten weeks to induce MASH-associated liver fibrosis, or a CDAA diet or a high fat diet (HFD) for shorter periods of time to induce early steatosis-associated alterations. Liver metastasis formation was assessed using melanoma cell lines B16F10Luc2 and Wt31. LSEC-specific GATA4 knockout mice (Gata4LSEC−KO/BL) developing MASH-like liver fibrosis without steatosis via a pathogenic angiocrine switch were included to compare the impact of liver fibrosis versus hepatic steatosis on hepatic melanoma metastasis. Bulk RNA-Seq of isolated LSECs from CDAA-fed and control mice was performed. Levels of adhesion molecules (VCAM1, ICAM1, E-selectin) were monitored, and ICAM1 and VCAM1 antibody therapy was employed. Results: Feeding a CDAA diet, in contrast to a HFD, led to increased metastasis before the development of liver fibrosis. Gata4LSEC−KO/BL mice characterized by vascular changes ensuing perisinusoidal liver fibrosis without steatosis also exhibited increased metastasis. Early molecular alterations in the hepatic vascular niche, rather than fibrosis or steatosis, correlated with metastasis, as shown by LSEC dedifferentiation and upregulation of endothelial adhesion molecules. The metastatic process in CDAA-fed mice was also dependent on the respective melanoma cell lines used and on the route of their metastatic spread. ICAM1 inhibition, but not VCAM1 inhibition reduced melanoma cell retention. Conclusion: We discovered that the hepatic vascular niche acts as a delicate sensor to even short-term nutritional alterations during the development of MASLD/MASH. The dynamic adaptations to the metabolic challenges of developing MASLD/MASH caused an early shift from the normal hepatic vascular niche to a pre-metastatic vascular niche that promoted hepatic melanoma metastasis in the context of cell-autonomous and acquired melanoma cell features. Altogether, our findings provide a potential avenue for angiotargeted therapies to prevent hepatic melanoma metastasis. [ABSTRACT FROM AUTHOR]

Introduction The coagulation factors von Willebrand factor (VWF) and factor VIII (FVIII) circulate in the plasma as a noncovalent complex, with VWF serving as a carrier to protect FVIII from [...], Quantitative abnormalities of the von Willebrand factor-factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF- dependent manner, and stabilin-2- deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates.

Introduction Endothelial cells (ECs) line the inside of all blood vessels, forming a structurally and functionally heterogeneous cell population (1, 2). The diversity of ECs along the segments of the [...], Microvascular endothelial cells (ECs) are increasingly recognized as organ-specific gatekeepers of their microenvironment. Microvascular ECs instruct neighboring cells in their organ-specific vascular niches through angiocrine factors, which include secreted growth factors (angiokines), extracellular matrix molecules, and transmembrane proteins. However, the molecular regulators that drive organ-specific microvascular transcriptional programs and thereby regulate angiodiversity are largely elusive. In contrast to other ECs, which form a continuous cell layer, liver sinusoidal ECs (LSECs) constitute discontinuous, permeable microvessels. Here, we have shown that the transcription factor GATA4 controls murine LSEC specification and function. LSEC-restricted deletion of Gata4 caused transformation of discontinuous liver sinusoids into continuous capillaries. Capillarization was characterized by ectopic basement membrane deposition, formation of a continuous EC layer, and increased expression of VE-cadherin. Correspondingly, ectopic expression of GATA4 in cultured continuous ECs mediated the downregulation of continuous EC-associated transcripts and upregulation of LSEC-associated genes. The switch from discontinuous LSECs to continuous ECs during embryogenesis caused liver hypoplasia, fibrosis, and impaired colonization by hematopoietic progenitor cells, resulting in anemia and embryonic lethality. Thus, GATA4 acts as master regulator of hepatic microvascular specification and acquisition of organ-specific vascular competence, which are indispensable for liver development. The data also establish an essential role of the hepatic microvasculature in embryonic hematopoiesis.

Introduction Tissue homeostasis and remodeling are accompanied by high turnover of all categories of biological macromolecules including proteins, proteoglycans, and polysaccharides as well as nucleic acids and lipids (1). During [...], Tissue homeostasis and remodeling are processes that involve high turnover of biological macromolecules. Many of the waste molecules that are by-products or degradation intermediates of biological macromolecule turnover enter the circulation and are subsequently cleared by liver sinusoidal endothelial cells (LSEC). Besides the mannose receptor, stabilin-1 and stabilin-2 are the major scavenger receptors expressed by LSEC. To more clearly elucidate the functions of stabilin-1 and -2, we have generated mice lacking stabilin-1, stabilin-2, or both stabilin-1 and -2 ([Stab1.sup.-/-][Stab2.sup.-/-] mice). Mice lacking either stabilin-1 or stabilin-2 were phenotypically normal; however, [Stab1.sup.-/-][Stab2.sup.-/-] mice exhibited premature mortality and developed severe glomerular fibrosis, while the liver showed only mild perisinusoidal fibrosis without dysfunction. Upon kidney transplantation intoWT mice, progression of glomerular fibrosis was halted, indicating the presence of profibrotic factors in the circulation of [Stab1.sup.-/-][Stab2.sup.-/-] mice. While plasma levels of known profibrotic cytokines were unaltered, clearance of the TGF-β family member growth differentiation factor 15 (GDF-15) was markedly impaired in [Stab1.sup.-/-][Stab2.sup.-/-] mice but not in either [Stab1.sup.-/-] or [Stab2.sup.-/-] mice, indicating that it is a common ligand of both stabilin-1 and stabilin-2. These data lead us to conclude that stabilin-1 and -2 together guarantee proper hepatic clearance of potentially noxious agents in the blood and maintain tissue homeostasis not only in the liver but also distant organs.

Chitinase‐like proteins (CLP) are chitin‐binding proteins that lack chitin hydrolyzing activity, but possess cytokine‐like and growth factor‐like properties, and play crucial role in intercellular crosstalk. Both human and mice express two members of CLP family: YKL‐40 and stabilin‐1 interacting chitinase‐like protein (SI‐CLP). Despite numerous reports indicating the role of YKL‐40 in the support of angiogenesis, tumor cell proliferation, invasion and metastasis, the role of its structurally related protein SI‐CLP in cancer was not reported. Using gain‐of‐function approach, we demonstrate in the current study that the expression of recombinant SI‐CLP in mouse TS/A mammary adenocarcinoma cells results in significant and persistent inhibition of in vivo tumor growth. Using quantitative immunohistochemistry, we show that on the cellular level this phenomenon is associated with reduced infiltration of tumor‐associated macrophages (TAMs), CD4+ and FoxP3+ cells in SI‐CLP expressing tumors. Gene expression analysis in TAM isolated from SI‐CLP‐expressing and control tumors demonstrated that SI‐CLP does not affect macrophage phenotype. However, SI‐CLP significantly inhibited migration of murine bone‐marrow derived macrophages and human primary monocytes toward monocyte‐recruiting chemokine CCL2 produced in the tumor microenvironment (TME). Mechanistically, SI‐CLP did not affect CCL2/CCR2 interaction, but suppressed cytoskeletal rearrangements in response to CCL2. Altogether, our data indicate that SI‐CLP functions as a tumor growth inhibitor in mouse breast cancer by altering cellular composition of TME and blocking cytokine‐induced TAM recruitment. Taking into consideration weak to absent expression of SI‐CLP in human breast cancer, it can be considered as a therapeutic protein to block TAM‐mediated support of breast tumor growth. What's new? Chitinase‐like proteins possess cytokine‐like properties and can manipulate cancer progression. Here the authors show that stabilin‐1 interacting chitinase‐like protein (SI‐CLP) inhibits the growth of murine mammary adenocarcinoma by altering the tumor microenvironment and reducing intratumoral macrophage infiltration. SI‐CLP is weakly expressed in human breast cancers and may function as a possible therapeutic agent to suppress breast cancer growth. [ABSTRACT FROM AUTHOR]