Hematopoietic stem and progenitor cells use podosomes to transcellularly cross the bone marrow endothelium

Timo Rademakers, Marieke Goedhart, Mark Hoogenboezem, Alexander García Ponce, Jos van Rijssel, Maryna Samus, Michael Schnoor, Stefan Butz, Stephan Huveneers, Dietmar Vestweber, Martijn A Nolte, Carlijn Voermans, Jaap D van Buul

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Bone marrow endothelium plays an important role in the homing of hematopoietic stem and progenitor cells upon transplantation, but surprisingly little is known on how the bone marrow endothelial cells regulate local permeability and hematopoietic stem and progenitor cells transmigration. We show that temporal loss of vascular endothelial-cadherin function promotes vascular permeability in BM, even upon low-dose irradiation. Loss of vascular endothelial-cadherin function also enhances homing of transplanted hematopoietic stem and progenitor cells to the bone marrow of irradiated mice although engraftment is not increased. Intriguingly, stabilizing junctional vascular endothelial-cadherin in vivo reduced bone marrow permeability, but did not prevent hematopoietic stem and progenitor cells migration into the bone marrow, suggesting that hematopoietic stem and progenitor cells use the transcellular migration route to enter the bone marrow. Indeed, using an in vitro migration assay, we show that human hematopoietic stem and progenitor cells predominantly cross bone marrow endothelium in a transcellular manner in homeostasis by inducing podosome-like structures. Taken together, vascular endothelial-cadherin is crucial for BM vascular homeostasis but dispensable for the homing of hematopoietic stem and progenitor cells. These findings are important in the development of potential therapeutic targets to improve hematopoietic stem and progenitor cell homing strategies.

Original languageEnglish
Pages (from-to)2746-2756
Number of pages11
JournalHaematologica-the Hematology Journal
Volume105
Issue number12
DOIs
Publication statusPublished - 1 Dec 2020
Externally publishedYes

Keywords

  • ADHESION
  • CD34(+) CELLS
  • DIAPEDESIS
  • IN-VIVO
  • LEUKOCYTE EXTRAVASATION
  • MIGRATION
  • NEUTROPHILS
  • ORGANIZATION
  • PERMEABILITY
  • VE-CADHERIN

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