Title | Chronic activation of endothelial MAPK disrupts hematopoiesis via NFKB dependent inflammatory stress reversible by SCGF. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Ramalingam P, Poulos MG, Lazzari E, Gutkin MC, Lopez D, Kloss CC, Crowley MJ, Katsnelson L, Freire AG, Greenblatt MB, Park CY, Butler JM |
Journal | Nat Commun |
Volume | 11 |
Issue | 1 |
Pagination | 666 |
Date Published | 2020 02 03 |
ISSN | 2041-1723 |
Keywords | Animals, Antigens, CD, Bone Marrow, Cadherins, Endothelial Cells, Female, Hematopoiesis, Hematopoietic Cell Growth Factors, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Inflammation, Lectins, C-Type, Male, Mice, Mitogen-Activated Protein Kinase Kinases, NF-kappa B, Signal Transduction, Transplantation, Autologous |
Abstract | Inflammatory signals arising from the microenvironment have emerged as critical regulators of hematopoietic stem cell (HSC) function during diverse processes including embryonic development, infectious diseases, and myelosuppressive injuries caused by irradiation and chemotherapy. However, the contributions of cellular subsets within the microenvironment that elicit niche-driven inflammation remain poorly understood. Here, we identify endothelial cells as a crucial component in driving bone marrow (BM) inflammation and HSC dysfunction observed following myelosuppression. We demonstrate that sustained activation of endothelial MAPK causes NF-κB-dependent inflammatory stress response within the BM, leading to significant HSC dysfunction including loss of engraftment ability and a myeloid-biased output. These phenotypes are resolved upon inhibition of endothelial NF-κB signaling. We identify SCGF as a niche-derived factor that suppresses BM inflammation and enhances hematopoietic recovery following myelosuppression. Our findings demonstrate that chronic endothelial inflammation adversely impacts niche activity and HSC function which is reversible upon suppression of inflammation. |
DOI | 10.1038/s41467-020-14478-8 |
Alternate Journal | Nat Commun |
PubMed ID | 32015345 |
PubMed Central ID | PMC6997369 |
Grant List | R01 AG065436 / AG / NIA NIH HHS / United States R01 CA204308 / CA / NCI NIH HHS / United States R01 HL133021 / HL / NHLBI NIH HHS / United States |
Related Faculty:
Matthew B. Greenblatt, M.D., Ph.D.