Evidence for platelet-derived transforming growth factor β1 as an early inducer of liver regeneration after hepatectomy in mice

Abstract

Platelets play a crucial role in tissue regeneration, and their involvement in liver regeneration is well-established. However, the specific contribution of platelet-derived Transforming Growth Factor Beta 1 (TGFβ1) to liver regeneration remains unexplored. This study investigated the role of platelet-derived TGFβ1 in initiating liver regeneration following 2/3 liver resection. Using platelet-specific TGFβ1 knockout (Plt.TGFβ1 KO) mice and wild-type littermates (Plt.TGFβ1 WT) as controls, the study assessed circulating levels and hepatic gene expression of TGFβ1, Platelet Factor 4 (PF4), and Thrombopoietin (TPO) at early time points post-hepatectomy (post-PHx). Hepatocyte proliferation was quantified through Ki67 staining and PCNA expression in total liver lysates at various intervals, and phosphohistone-H3 (PHH3) staining was employed to mark mitotic cells. Circulating levels of hepatic mitogens, Hepatocyte Growth Factor (HGF), and Interleukin-6 (IL6) were also assessed. Results revealed that platelet-TGFβ1 deficiency significantly reduced total plasma TGFβ1 levels at 5 h post-PHx in Plt.TGFβ1 KO mice compared to controls. While circulating PF4 levels, liver platelet recruitment and activation appeared normal at early time points, Plt.TGFβ1 KO mice showed more stable circulating platelet numbers with higher numbers at 48 h post-PHx. Notably, hepatocyte proliferation was significantly reduced in Plt.TGFβ1 KO mice. The results show that a lack of TGFβ1 in platelets leads to an unbalanced expression of IL6 in the liver and to strongly increased HGF levels 48 h after liver resection, and yet liver regeneration remains reduced. The study identifies platelet-TGFβ1 as a regulator of hepatocyte proliferation and platelet homeostasis in the early stages of liver regeneration.