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

• Published in: Cell stem cell 2009-03, Vol.4 (3), p.263-274
• Main Authors: Hooper, Andrea T., Butler, Jason M., Nolan, Daniel J., Kranz, Andrea, Iida, Kaoruko, Kobayashi, Mariko, Kopp, Hans-Georg, Shido, Koji, Petit, Isabelle, Yanger, Kilangsungla, James, Daylon, Witte, Larry, Zhu, Zhenping, Wu, Yan, Pytowski, Bronislaw, Rosenwaks, Zev, Mittal, Vivek, Sato, Thomas N., Rafii, Shahin
• Format: Article
• Language: English
• Subjects: Animals; Ataxin-1; Ataxins; Biological and medical sciences; Blood Vessels - physiology; Bone Marrow - blood supply; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Endothelium, Vascular - radiation effects; Fundamental and applied biological sciences. Psychology; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - physiology; Mice; Mice, Knockout; Molecular and cellular biology; Nerve Tissue Proteins - biosynthesis; Nuclear Proteins - biosynthesis; Regeneration; Sequence Deletion; Signal Transduction; STEMCELL; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Whole-Body Irradiation
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2009.01.006

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.