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Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells.

TitleEngraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells.
Publication TypeJournal Article
Year of Publication2009
AuthorsHooper AT, Butler JM, Nolan DJ, Kranz A, Iida K, Kobayashi M, Kopp H-G, Shido K, Petit I, Yanger K, James D, Witte L, Zhu Z, Wu Y, Pytowski B, Rosenwaks Z, Mittal V, Sato TN, Rafii S
JournalCell Stem Cell
Volume4
Issue3
Pagination263-74
Date Published2009 Mar 6
ISSN1875-9777
KeywordsAnimals, Ataxin-1, Ataxins, Blood Vessels, Bone Marrow, Endothelium, Vascular, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Mice, Mice, Knockout, Nerve Tissue Proteins, Nuclear Proteins, Regeneration, Sequence Deletion, Signal Transduction, Vascular Endothelial Growth Factor Receptor-2, Whole-Body Irradiation
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.

DOI10.1016/j.stem.2009.01.006
Alternate JournalCell Stem Cell
PubMed ID19265665
PubMed Central IDPMC3228275
Grant ListP01 HL059312 / HL / NHLBI NIH HHS / United States
P01 HL059312-060006 / HL / NHLBI NIH HHS / United States
P01 HL059312-070006 / HL / NHLBI NIH HHS / United States
P01 HL059312-080006 / HL / NHLBI NIH HHS / United States
P01 HL059312-090006 / HL / NHLBI NIH HHS / United States
P01 HL059312-100006 / HL / NHLBI NIH HHS / United States
P01 HL067839 / HL / NHLBI NIH HHS / United States
P01 HL067839-010004 / HL / NHLBI NIH HHS / United States
P01 HL067839-020004 / HL / NHLBI NIH HHS / United States
P01 HL067839-030004 / HL / NHLBI NIH HHS / United States
P01 HL067839-040004 / HL / NHLBI NIH HHS / United States
P01 HL067839-050004 / HL / NHLBI NIH HHS / United States
P01 HL072942 / HL / NHLBI NIH HHS / United States
P01 HL072942-010004 / HL / NHLBI NIH HHS / United States
P50 HL084936 / HL / NHLBI NIH HHS / United States
P50 HL084936-010003 / HL / NHLBI NIH HHS / United States
P50 HL084936-020003 / HL / NHLBI NIH HHS / United States
P50 HL084936-030003 / HL / NHLBI NIH HHS / United States
P50 HL084936-040003 / HL / NHLBI NIH HHS / United States
R01 HL058707 / HL / NHLBI NIH HHS / United States
R01 HL058707-03 / HL / NHLBI NIH HHS / United States
R01 HL058707-04 / HL / NHLBI NIH HHS / United States
R01 HL061849 / HL / NHLBI NIH HHS / United States
R01 HL061849-02 / HL / NHLBI NIH HHS / United States
R01 HL061849-03 / HL / NHLBI NIH HHS / United States
R01 HL061849-03S1 / HL / NHLBI NIH HHS / United States
R01 HL061849-04 / HL / NHLBI NIH HHS / United States
R01 HL061849-05 / HL / NHLBI NIH HHS / United States
R01 HL075234 / HL / NHLBI NIH HHS / United States
R01 HL075234-01 / HL / NHLBI NIH HHS / United States
R01 HL075234-02 / HL / NHLBI NIH HHS / United States
R01 HL075234-03 / HL / NHLBI NIH HHS / United States
R01 HL075234-04 / HL / NHLBI NIH HHS / United States
R01 HL097797 / HL / NHLBI NIH HHS / United States
R01 HL097797-01 / HL / NHLBI NIH HHS / United States
R01 HL097797-02 / HL / NHLBI NIH HHS / United States
R01 HL097797-03 / HL / NHLBI NIH HHS / United States
R21 HL083222 / HL / NHLBI NIH HHS / United States
R21 HL083222-01 / HL / NHLBI NIH HHS / United States
R21 HL083222-02 / HL / NHLBI NIH HHS / United States
U01 HL066952 / HL / NHLBI NIH HHS / United States
U01 HL066952-010002 / HL / NHLBI NIH HHS / United States
U01 HL066952-020002 / HL / NHLBI NIH HHS / United States
U01 HL066952-030002 / HL / NHLBI NIH HHS / United States
U01 HL066952-040002 / HL / NHLBI NIH HHS / United States
U01 HL066952-050002 / HL / NHLBI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
/ / Howard Hughes Medical Institute / United States