Neuropilin 1 regulates bone marrow vascular regeneration and hematopoietic reconstitution.

Autor:	Termini CM; Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA.; Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA.; Department of Orthopedic Surgery, UCLA, Los Angeles, CA, USA., Pang A; Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA., Fang T; Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA.; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA., Roos M; Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA.; Eli and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA.; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA., Chang VY; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.; Pediatric Hematology/Oncology, UCLA, Los Angeles, CA, USA., Zhang Y; Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA.; Molecular Biology Institute, UCLA, Los Angeles, CA, USA., Setiawan NJ; Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA., Signaevskaia L; Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA., Li M; Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA., Kim MM; Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA., Tabibi O; Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA., Lin PK; Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA., Sasine JP; Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA.; Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA., Chatterjee A; Department of Biomedical Sciences, Research Division of Immunology, Los Angeles, USA., Murali R; Department of Biomedical Sciences, Research Division of Immunology, Los Angeles, USA., Himburg HA; Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA., Chute JP; Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA. john.chute@cshs.org.; Regenerative Medicine Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA. john.chute@cshs.org.; Samuel Oschin Cancer Center, Cedars Sinai Medical Center, Los Angeles, CA, USA. john.chute@cshs.org.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2021 Nov 30; Vol. 12 (1), pp. 6990. Date of Electronic Publication: 2021 Nov 30.
DOI:	10.1038/s41467-021-27263-y
Abstrakt:	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. (© 2021. The Author(s).)
Databáze:	MEDLINE
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