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.
Highlights
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
Utilizing an ex vivo niche model system, we have previously demonstrated that endothelial MAPK activation drives myeloid-biased differentiation of co-cultured HSCs at the expense of their self-renewal, features that are suggestive of an inflammatory stress[15]
To activate MAPK signaling in endothelial cells (ECs), 6- to 10-week-old male and female mice were maintained on tamoxifen-impregnated feed (250 mg/kg) for 4 weeks and were allowed to recover for 4 weeks before experimental analysis
Summary
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. 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. In the context of hematopoiesis, inflammatory signals play key roles during diverse processes including embryonic specification of the hematopoietic stem cell (HSC) during development, emergency granulopoiesis during infections, and hematopoietic regeneration following transplantation[4,5,6,7,8]. Nuclear factor-κB (NF-κB) and MAPK are the principal signaling pathways regulating chronic inflammatory responses within ECs25 Their role in modulating inflammation within the BM endothelial niche and the concomitant impact on HSC function remains unexplored. We sought to determine whether endothelial MAPK activation impacts BM inflammation, niche activity, and HSC function
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