Engraftment and Reconstitution of Hematopoiesis Is Dependent on VEGFR2-Mediated Regeneration of Sinusoidal Endothelial Cells

Andrea T. Hooper, Jason M. Butler, Daniel J. Nolan, Andrea Kranz, Kaoruko Iida, Mariko Kobayashi, Hans Georg Kopp, Koji Shido, Isabelle Petit, Kilangsungla Yanger, Daylon James, Larry Witte, Zhenping Zhu, Yan Wu, Bronislaw Pytowski, Zev Rosenwaks, Vivek Mittal, Thomas N. Sato, Shahin Rafii

Research output: Contribution to journalArticle

397 Scopus citations

Abstract

Myelosuppression damages the bone marrow (BM) vascular niche, but it is unclear how regeneration of bone marrow vessels contributes to engraftment of transplanted hematopoietic stem and progenitor cells (HSPCs) and restoration of hematopoiesis. We found that chemotherapy and sublethal irradiation induced minor regression of BM sinusoidal endothelial cells (SECs), while lethal irradiation induced severe regression of SECs and required BM transplantation (BMT) for regeneration. Within the BM, VEGFR2 expression specifically demarcated a continuous network of arterioles and SECs, with arterioles uniquely expressing Sca1 and SECs uniquely expressing VEGFR3. Conditional deletion of VEGFR2 in adult mice blocked regeneration of SECs in sublethally irradiated animals and prevented hematopoietic reconstitution. Similarly, inhibition of VEGFR2 signaling in lethally irradiated wild-type mice rescued with BMT severely impaired SEC reconstruction and prevented engraftment and reconstitution of HSPCs. Therefore, regeneration of SECs via VEGFR2 signaling is essential for engraftment of HSPCs and restoration of hematopoiesis.

Original languageEnglish (US)
Pages (from-to)263-274
Number of pages12
JournalCell Stem Cell
Volume4
Issue number3
DOIs
StatePublished - Mar 6 2009

Keywords

  • STEMCELL

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

Fingerprint Dive into the research topics of 'Engraftment and Reconstitution of Hematopoiesis Is Dependent on VEGFR2-Mediated Regeneration of Sinusoidal Endothelial Cells'. Together they form a unique fingerprint.

Cite this