Chronic activation of endothelial MAPK disrupts hematopoiesis via NFKB dependent inflammatory stress reversible by SCGF

Autor: Matthew B. Greenblatt, Elisa Lazzari, David Lopez, Ana G. Freire, Christopher C. Kloss, Michael C. Gutkin, Lizabeth Katsnelson, Christopher Y. Park, Michael J. Crowley, Pradeep Ramalingam, Michael G. Poulos, Jason M. Butler
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
MAPK/ERK pathway
Male
medicine.medical_treatment
General Physics and Astronomy
Hematopoietic stem cell transplantation
Mice
0302 clinical medicine
Bone Marrow
Autotransplantation
lcsh:Science
Multidisciplinary
Haematopoietic stem cells
Hematopoietic Stem Cell Transplantation
NF-kappa B
Hematopoietic stem cell
Cadherins
3. Good health
Haematopoiesis
medicine.anatomical_structure
030220 oncology & carcinogenesis
Female
medicine.symptom
Signal transduction
Signal Transduction
Science
Inflammation
Hematopoietic Cell Growth Factors
Transplantation
Autologous
General Biochemistry
Genetics and Molecular Biology
Article
03 medical and health sciences
Antigens
CD
medicine
Animals
Lectins
C-Type
Mitogen-Activated Protein Kinase Kinases
business.industry
Endothelial Cells
General Chemistry
Hematopoietic Stem Cells
Hematopoiesis
Transplantation
030104 developmental biology
Cancer research
lcsh:Q
Bone marrow
business
Stem-cell niche
Zdroj: Nature Communications
Nature Communications, Vol 11, Iss 1, Pp 1-20 (2020)
ISSN: 2041-1723
Popis: 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.
Myelosuppressive injuries lead to chronic MAPK activation and impair blood reconstitution. Here, the authors show that chronic activation endothelial MAPK impairs hematopoietic stem cell (HSC) function through NFkB signaling, and that post-myelosuppressive HSC defects can be reversed by administration of Stem Cell Growth Factor SCGFa.
Databáze: OpenAIRE
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