Primary peritoneal mast cells (PMC) reduce the fibrogenic response of hepatic stellate cells while inducing caspase 3 cleavage and activity

Background: Mast cells (MCs) are recruited to the liver during fibrosis and induce detachment- dependent apoptosis in mouse embryonic fibroblasts [1]. We have previously shown that co-culture of a murine MC line (L138.8A) with the murine hepatic stellate cell line HSC/Col-GFP [2] leads to a strong reduction of the fibrotic response in HSC by affecting several aspects of TGF-β signaling [3].

Methods and Results: We show here that L138.8A cells are able to reduce fibrogenic responses in primary rat HSC as well. Primary murine Peritoneum-derived MC were isolated and cultured as described before [4]. Similar effects on attenuation of pro-fibrogenic responses were observed in HSC/Col-GFP when co-cultured with primary peritoneal MC (PMC). In addition the expression of cyclin A is reduced pointing towards a lower cell cycle/proliferation rate. Moreover under optimal conditions (IL-3 and SCF supplementation), PMC induce caspase 3 cleavage which is accompanied by a reduction in Poly (ADP-ribose) polymerase (PARP) abundance. These effects are paralleled by a strong increase in STAT5 activity.

Conclusions: Primary mouse PMC reduce the fibrogenic and proliferative response while inducing the apoptotic response in HSC. Our study suggests that targeting the activity of PMC in hepatic fibrogenesis may provide therapeutic benefits during phases of liver injury.

References:

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[2] Meurer SK, Alsamman M, Sahin H, Wasmuth HE, Kisseleva T, Brenner DA, Trautwein C, Weiskirchen R, Scholten D. (2013) Overexpression of endoglin modulates TGF-β1-signalling pathways in a novel immortalized mouse hepatic stellate cell line. PLoS ONE 8(2):e56116.

[3] Meurer SK, Neß M, Weiskirchen R. (2015) Mast cells inhibit activation and profibrogenic activities of hepatic stellate cells. Z Gastroenterol, 53:1540.

[4] Meurer SK, Neß M, Weiskirchen S, Kim P, Tag CG, Kauffmann M, Huber M, Weiskirchen R. (2016) Isolation of mature (peritoneum-derived) mast cells and immature (bone marrow-derived) mast cell precursors from mice. PLoS ONE 11(6): e0158104.