Abstract
The roles and interactions of platelets and liver sinusoidal endothelial cells in liver regeneration are unclear, and the trigger that initiates hepatocyte proliferation is unknown. We aimed to identify the key factors released by activated platelets that induce liver sinusoidal endothelial cells to produce interleukin-6 (IL-6), a cytokine implicated in the early phase of liver regeneration. We characterized the releasate of activated platelets inducing the in vitro production of IL-6 by mouse liver sinusoidal endothelial cells and observed that the stimulating factor was a thermolabile protein. Following gel filtration, a single fraction of activated platelet releasate induced a maximal IL-6 secretion by liver sinusoidal endothelial cells (90.2 ± 13.9 versus control with buffer, 9.0 ± 0.8 pg/mL, p < 0.05). Mass spectroscopy analysis of this fraction, followed by in silico processing, resulted in a reduced list of 18 candidates. Several proteins from the list were tested, and only recombinant transforming growth factor β1 (TGF-β1) resulted in an increased IL-6 production up to 242.7 ± 30.5 pg/mL, which was comparable to non-fractionated platelet releasate effect. Using neutralizing anti-TGF-β1 antibody or a TGF-β1 receptor inhibitor, IL-6 production by liver sinusoidal endothelial cells was dramatically reduced. These results support a role of platelet TGF-β1 β1 in the priming phase of liver regeneration.
Highlights
Despite their lack of nuclei, platelets are implicated in numerous functions, including tissue regenerative processes following their activation, which induces their degranulation and release ofCells 2020, 9, 1311; doi:10.3390/cells9051311 www.mdpi.com/journal/cellsCells 2020, 9, 1311 platelets microparticles (PMP) [1,2,3]
activated platelets releasate (APR) from different platelet concentrations to investigate whether liver sinusoidal endothelial cells (LSEC) were able to increase IL-6 production
We demonstrated that LSEC still increased their IL-6 production up to a mean fold increase
Summary
Despite their lack of nuclei, platelets are implicated in numerous functions, including tissue regenerative processes following their activation, which induces their degranulation and release of. Cells 2020, 9, 1311 platelets microparticles (PMP) [1,2,3]. Platelets have been proposed as actors of liver regeneration, the precise mechanisms have not been unveiled. Platelets accumulate in sinusoids or are translocated into the space of Disse, which separates the liver sinusoidal endothelial cells (LSEC) lining from hepatocytes [2]. Platelets may act through the release of granule-derived proliferative factors or by mechanisms such as platelet internalization by hepatocytes [4] or LSEC [5,6]. Platelets act at several levels in liver regeneration. Direct effects on hepatocyte proliferation were demonstrated through the release of dense granule-derived serotonin [7,8] and α-granules-derived hepatocyte growth factor, vascular endothelial growth factor and insulin-like growth factor-1 [9]
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