title: Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells.
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.
authors.affiliation: Howard Hughes Medical Institute, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Hooper
authors.forename: Jason M
authors.initials: JM
authors.lastname: Butler
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Nolan
authors.forename: Andrea
authors.initials: A
authors.lastname: Kranz
authors.forename: Kaoruko
authors.initials: K
authors.lastname: Iida
authors.forename: Mariko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Kopp
authors.forename: Koji
authors.initials: K
authors.lastname: Shido
authors.forename: Isabelle
authors.initials: I
authors.lastname: Petit
authors.forename: Kilangsungla
authors.initials: K
authors.lastname: Yanger
authors.forename: Daylon
authors.initials: D
authors.lastname: James
authors.forename: Larry
authors.initials: L
authors.lastname: Witte
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Bronislaw
authors.initials: B
authors.lastname: Pytowski
authors.forename: Zev
authors.initials: Z
authors.lastname: Rosenwaks
authors.forename: Vivek
authors.initials: V
authors.lastname: Mittal
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Sato
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D001808:Blood Vessels / Q000502:physiology; D001853:Bone Marrow / Q000098:blood supply*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000096:biosynthesis; D012038:Regeneration; D017384:Sequence Deletion; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D014916:Whole-Body Irradiation
chemical_list: D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2