An irradiated marrow niche reveals a small noncollagenous protein mediator of homing, dermatopontin

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

Research output: Contribution to journalArticlepeer-review

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 zebrafish marrow niche cells following conditioning. We determined that the noncollagenous protein extracellular matrix related protein dermatopontin (Dpt) was upregulated sevenfold in response to irradiation. Studies in mice revealed DPT induction with radiation and lipopolysaccharide exposure. Interestingly, we found that coincubation of zebrafish or murine hematopoietic cells with recombinant DPT impedes hematopoietic stem and progenitor cell homing by 50% and 86%, respectively. Similarly, this translated into a 24% reduction in long-term engraftment (vs control; P = .01). We found DPT to interact with VLA-4 and block hematopoietic cell-endothelial cell adhesion and transendothelial migration. Finally, a DPT-knockout mouse displayed a 60% increase in the homing of hematopoietic cells vs wild-type mice (P = .03) with a slight improvement in long-term lin-SCA1+cKIT+-SLAM cell engraftment (twofold; P = .04). These data show that the extracellular matrix-related protein DPT increases with radiation and transiently impedes the transendothelial migration of hematopoietic cells to the marrow.

Original languageEnglish (US)
Pages (from-to)3609-3622
Number of pages14
JournalBlood Advances
Volume5
Issue number18
DOIs
StatePublished - Sep 28 2021

Bibliographical note

Funding Information:
This work was supported in part by the National Institutes of Health, National Heart, Lung, and Blood Institute (K08HL108998, R03HL133318), an American Society of Hematology Bridge Grant, and the State of Minnesota, through a Regenerative Medicine Minnesota Award (T.C.L). The Zebrafish Atlas was supported by National Institutes of Health, National Center for Research Resources grant R24 RR01744, the Jake Gittlen Cancer Research Foundation, and the PA Tobacco Settlement Fund.

Publisher Copyright:
© 2021 by The American Society of Hematology.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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