Neuropilin 1 regulates bone marrow vascular regeneration and hematopoietic reconstitution. Nat Commun 2021 Nov 30;12(1):6990
Date
12/02/2021Pubmed ID
34848712Pubmed Central ID
PMC8635308DOI
10.1038/s41467-021-27263-yScopus ID
2-s2.0-85120176028 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
Ionizing radiation and chemotherapy deplete hematopoietic stem cells and damage the vascular niche wherein hematopoietic stem cells reside. Hematopoietic stem cell regeneration requires signaling from an intact bone marrow (BM) vascular niche, but the mechanisms that control BM vascular niche regeneration are poorly understood. We report that BM vascular endothelial cells secrete semaphorin 3 A (SEMA3A) in response to myeloablation and SEMA3A induces p53 - mediated apoptosis in BM endothelial cells via signaling through its receptor, Neuropilin 1 (NRP1), and activation of cyclin dependent kinase 5. Endothelial cell - specific deletion of Nrp1 or Sema3a or administration of anti-NRP1 antibody suppresses BM endothelial cell apoptosis, accelerates BM vascular regeneration and concordantly drives hematopoietic reconstitution in irradiated mice. In response to NRP1 inhibition, BM endothelial cells increase expression and secretion of the Wnt signal amplifying protein, R spondin 2. Systemic administration of anti - R spondin 2 blocks HSC regeneration and hematopoietic reconstitution which otherwise occurrs in response to NRP1 inhibition. SEMA3A - NRP1 signaling promotes BM vascular regression following myelosuppression and therapeutic blockade of SEMA3A - NRP1 signaling in BM endothelial cells accelerates vascular and hematopoietic regeneration in vivo.
Author List
Termini CM, Pang A, Fang T, Roos M, Chang VY, Zhang Y, Setiawan NJ, Signaevskaia L, Li M, Kim MM, Tabibi O, Lin PK, Sasine JP, Chatterjee A, Murali R, Himburg HA, Chute JPAuthor
Heather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Bone Marrow
Bone Marrow Cells
Cyclin-Dependent Kinase 5
Female
Hematopoietic Stem Cells
Male
Mice
Mice, Inbred C57BL
Neuropilin-1
Regeneration
Semaphorin-3A
Signal Transduction
Transcriptome
Wnt Proteins
