Splenic serum from portal hypertensive patients enhances liver stem cell proliferation and self-renewal via the IGF-II/ERK signaling pathway.

BACKGROUND

Hypersplenism is a serious complication of portal hypertension (PH) and can affect the prognosis of liver disease. Liver stem cells (LSCs) are involved in liver regeneration and hepatocarcinogenesis after liver cirrhosis.

AIM: To explore the effects and mechanism of the spleen on the proliferation and differentiation of LSCs in PH due to liver cirrhosis.

METHODS

Fetal liver stem cells (FLSCs) were treated with splenic serum from liver cirrhosis patients with hypersplenism and control serum from healthy volunteers, and the proliferation, self-renewal, and IGF-II/ERK signaling pathway of FLSCs were then evaluated.

RESULTS

We found that splenic serum from PH patients promoted FLSC proliferation, colony formation, and Ki-67 expression in vitro. Splenic serum from PH also enhanced FLSC spheroid formation in vitro. Mechanistically, we determined that insulin-like growth factor (IGF)-II concentration was elevated in splenic serum from PH patients and could promote FLSC proliferation and self-renewal. Furthermore, both IGF-II and splenic serum from PH patients enhanced ERK signaling activation through IGF-I receptor (IGF-I R) in FLSCs. Consistently, blocking IGF-I R or ERK signaling could attenuate the effects of splenic serum from PH patients on FLSCs.

CONCLUSIONS

The spleen in PH patients promotes FLSC proliferation and self-renewal through the IGF-II/ERK signaling pathway.