Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells.
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.
Hooper
Andrea T
AT
Howard Hughes Medical Institute, Weill Cornell Medical College, New York, NY 10065, USA.
Butler
Jason M
JM
Nolan
Daniel J
DJ
Kranz
Andrea
A
Iida
Kaoruko
K
Kobayashi
Mariko
M
Kopp
Hans-Georg
HG
Shido
Koji
K
Petit
Isabelle
I
Yanger
Kilangsungla
K
James
Daylon
D
Witte
Larry
L
Zhu
Zhenping
Z
Wu
Yan
Y
Pytowski
Bronislaw
B
Rosenwaks
Zev
Z
Mittal
Vivek
V
Sato
Thomas N
TN
Rafii
Shahin
S
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
D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2