An irradiated marrow niche reveals a small non-collagenous protein mediator of homing, dermatopontin

Abstract

Hematopoietic cell homing after hematopoietic cell transplant (HCT) is governed by several pathways involving marrow niche cells that are evoked after pre-HCT conditioning. To understand the factors that play a role in homing, we performed expression analysis on the zebrafish marrow niche cells following conditioning. We determined that the non-collagenous protein extracellular matrix related protein dermatopontin (Dpt) was upregulated seven-fold in response to irradiation. Studies in mice revealed DPT induction both with radiation and lipopolysaccharide exposure. Interestingly, we found that co-incubation of zebrafish or murine hematopoietic cells with rDPT impedes hematopoietic stem and progenitor cell homing by 50% and 86%, respectively. Similarly, this translated into a 24% reduction in long term engraftment (versus control, p = 0.01). We found DPT to interact with VLA-4 and block hematopoietic - endothelial cell adhesion and transendothelial migration. Finally, a DPT knockout mouse displayed a 60% increase in homing of hematopoietic cells versus wildtype (p = 0.03) with slight improvement in long-term LSK-SLAM engraftment (2-fold, p = 0.04). These data show that the extracellular matrix (ECM)-related protein DPT increases with radiation and transiently impedes the transendothelial migration of hematopoietic cells to the marrow.

Dermatopontin Influences the Development of Obesity-Associated Colon Cancer by Changes in the Expression of Extracellular Matrix Proteins

“…Since inflammation predisposes to the development of cancer and promotes all stages of tumourigenesis [ 39 ] and DPT was previously described as a tumour suppressor molecule, our findings suggest a compensatory mechanism whereby DPT expression may increase in the context of strong inflammation, trying to avoid or minimize cell damage exhibiting its tissue-repairing functions; however, whether DPT is an inflammation driver or a responder still remains unknown. A similar response was observed after an inflammatory insult in zebrafish and mice where DPT levels were increased after myeloablative radiation [ 40 ]. Furthermore, plasma levels of DPT also increase after chemotherapy treatments [ 40 ].…”

“…A similar response was observed after an inflammatory insult in zebrafish and mice where DPT levels were increased after myeloablative radiation [ 40 ]. Furthermore, plasma levels of DPT also increase after chemotherapy treatments [ 40 ]. Importantly, TGF-β treatment induced an increase in the mRNA levels of DPT.…”

“…VEGFA expression was increased after the stimulation with DPT suggesting that DPT may favour tissue repair by facilitating the angiogenesis process. Importantly, changes in gene expression levels were observed after the treatment with the highest concentration suggesting a threshold in DPT levels that would explain the dual behaviour that this molecule exhibits; however, not only the concentrations of this molecule may determine its biological effect, but also the availability and expression levels of the receptors to which DPT binds; these interactions can result in the activation of certain intracellular pathways or in the suppression of the functions of the receptor, as in the case of binding to the receptor VLA-4 [ 40 ]. Based on these data, we presume that DPT influences ECM remodelling in HT-29 cells by modulating the expression of certain types of collagens and molecules that are dysregulated in inflammation, obesity or cancer.…”