VEGF-C protects the integrity of the bone marrow perivascular niche in mice
| Autor: | Kari Alitalo, Veli-Matti Leppänen, Harri Nurmi, David T. Scadden, Hanna K. A. Mikkola, Shuo Chen, Michael Jeltsch, Lev Silberstein, Shentong Fang |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Immunology Cell Vascular Endothelial Growth Factor C Gene Expression Bone Marrow Cells Mice Transgenic Biology Biochemistry Models Biological Viral vector Immunophenotyping 03 medical and health sciences Mice 0302 clinical medicine Vascular Biology Bone Marrow medicine Animals RNA Messenger Stem Cell Niche Regeneration (biology) Endothelial Cells Cell Biology Hematology Cell biology Hematopoiesis Transplantation Haematopoiesis 030104 developmental biology medicine.anatomical_structure Vascular endothelial growth factor C Receptors Leptin Bone marrow Stem cell 030217 neurology & neurosurgery Biomarkers Protein Binding |
| Zdroj: | Blood |
| Popis: | Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) stem cell niche, which provides a vital source of HSC regulatory signals. Radiation and chemotherapy disrupt the HSC niche, including its sinusoidal vessels and perivascular cells, contributing to delayed hematopoietic recovery. Thus, identification of factors that can protect the HSC niche during an injury could offer a significant therapeutic opportunity to improve hematopoietic regeneration. In this study, we identified a critical function for vascular endothelial growth factor-C (VEGF-C), that of maintaining the integrity of the BM perivascular niche and improving BM niche recovery after irradiation-induced injury. Both global and conditional deletion of Vegfc in endothelial or leptin receptor–positive (LepR+) cells led to a disruption of the BM perivascular niche. Furthermore, deletion of Vegfc from the microenvironment delayed hematopoietic recovery after transplantation by decreasing endothelial proliferation and LepR+ cell regeneration. Exogenous administration of VEGF-C via an adenoassociated viral vector improved hematopoietic recovery after irradiation by accelerating endothelial and LepR+ cell regeneration and by increasing the expression of hematopoietic regenerative factors. Our results suggest that preservation of the integrity of the perivascular niche via VEGF-C signaling could be exploited therapeutically to enhance hematopoietic regeneration. |
| Databáze: | OpenAIRE |
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