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

2021; Elsevier BV; Linguagem: Inglês

10.1182/bloodadvances.2021004475

2473-9537

Ashley C. Kramer, Yuliana Astuti, Alexis K. Elfstrum, Michael Jonathan Lehrke, Jakub Tolar, Bruce R. Blazar, Amanda L. Blake, Mandy Taisto, Justin W. Furcich, Erin E. Nolan, Wilaiwan Durose, Beau R. Webber, Athena Geisness, David K. Wood, Troy C. Lund,

Virus-based gene therapy research

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.