Abstract
BackgroundHeparanase, endoglycosidase that cleaves heparan sulfate side chains of heparan sulfate proteoglycans, plays important roles in cancer metastasis, angiogenesis and inflammation.Design and MethodsApplying a mouse model of bone marrow transplantation and transgenic mice over-expressing heparanase, we evaluated the effect of heparanase on the engraftment process and the development of graft-versus-host disease.ResultsAnalysis of F1 mice undergoing allogeneic bone marrow transplantation from C57BL/6 mice demonstrated a better and faster engraftment in mice receiving cells from donors that were pretreated with heparanase. Moreover, heparanase treated recipient F1 mice showed only a mild appearance of graft-versus-host disease and died 27 days post transplantation while control mice rapidly developed signs of graft-versus-host disease (i.e., weight loss, hair loss, diarrhea) and died after 12 days, indicating a protective effect of heparanase against graft-versus-host disease. Similarly, we applied transgenic mice over-expressing heparanase in most tissues as the recipients of BMT from C57BL/6 mice. Monitoring clinical parameters of graft-versus-host disease, the transgenic mice showed 100% survival on day 40 post transplantation, compared to only 50% survival on day 14, in the control group. In vitro and in vivo studies revealed that heparanase inhibited T cell function and activation through modulation of their cytokine repertoire, indicated by a marked increase in the levels of Interleukin-4, Interleukin-6 and Interleukin-10, and a parallel decrease in Interleukin-12, tumor necrosis factor-alfa and interferon-gamma. Using point mutated inactive enzyme, we found that the shift in cytokine profile was independent of heparanase enzymatic activity.ConclusionsOur results indicate a significant role of heparanase in bone marrow transplantation biology, facilitating engraftment and suppressing graft-versus-host disease, apparently through an effect on T cell activation and cytokine production pattern.
Highlights
Heparan sulfate proteoglycans (HSPGs) are ubiquitous macromolecules associated with the cell surface and extracellular matrix (ECM) of a wide range of cells [1,2,3]
We have found a marked increase in the number of hematopoietic stem cells in the bone marrow (BM) of heparanase over-expressing transgenic (Hpa-tg) mice compared to wild type control mice [31]
Having demonstrated a protective effect of heparanase against graft-versus-host disease (GVHD) in mice, and in an attempt to elucidate the mode of heparanase action in this process, we investigated its effect on activation of lymphocytes
Summary
Heparan sulfate proteoglycans (HSPGs) are ubiquitous macromolecules associated with the cell surface and extracellular matrix (ECM) of a wide range of cells [1,2,3]. HS chains, unique in their ability to bind a multitude of proteins, ensure that a wide variety of bioactive molecules bind to the cell surface and ECM and thereby function in the control of diverse normal and pathological processes [1,4,5]. The involvement of glycosaminoglycan (e.g., heparan sulfate) degrading enzymes (e.g., heparanase) was underestimated, primarily due to a lack of appropriate molecular probes to explore their causative role in cell-ECM interactions and related effects. Heparanase, endoglycosidase that cleaves heparan sulfate side chains of heparan sulfate proteoglycans, plays important roles in cancer metastasis, angiogenesis and inflammation
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