期刊
STEM CELL REVIEWS AND REPORTS
卷 16, 期 5, 页码 954-967出版社
SPRINGER
DOI: 10.1007/s12015-020-10005-w
关键词
Nlrp3 inflammasome; Purinergic signaling; Extracellular nucleotides; Complement cascade; Stem cell homing; Stem cell engraftment; Bone marrow sterile inflammation
资金
- NIH [R01 HL124266, 2R01 DK074720, R01HL112788, T32 HL134644]
- Stella and Henry Endowment
- OPUS grant [DEC-2016/23/B/NZ3/03157]
- University of Kentucky COBRE Early Career Program [P20 GM103527]
Fast and efficient homing and engraftment of hematopoietic stem progenitor cells (HSPCs) is crucial for positive clinical outcomes from transplantation. We found that this process depends on activation of the Nlrp3 inflammasome, both in the HSPCs to be transplanted and in the cells in the recipient bone marrow (BM) microenvironment. For the first time we provide evidence that functional deficiency in the Nlrp3 inflammasome in transplanted cells or in the host microenvironment leads to defective homing and engraftment. At the molecular level, functional deficiency of the Nlrp3 inflammasome in HSPCs leads to their defective migration in response to the major BM homing chemoattractant stromal-derived factor 1 (SDF-1) and to other supportive chemoattractants, including sphingosine-1-phosphate (S1P) and extracellular adenosine triphosphate (eATP). We report that activation of the Nlrp3 inflammasome increases autocrine release of eATP, which promotes incorporation of the CXCR4 receptor into membrane lipid rafts at the leading surface of migrating cells. On the other hand, a lack of Nlrp3 inflammasome expression in BM conditioned for transplantation leads to a decrease in expression of SDF-1 and danger-associated molecular pattern molecules (DAMPs), which are responsible for activation of the complement cascade (ComC), which in turn facilitates the homing and engraftment of HSPCs.
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