Abstract
BackgroundCirculating cirrhotic endothelial progenitor cells (EPC) interact with both liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC) and promote angiogenesis in vitro. This study evaluated the effect of cirrhotic and control EPCs on hepatic angiogenesis, microcirculation, and fibrosis in vivo in rat models of cirrhosis.MethodologyAnimal models of cirrhosis were prepared by bile duct ligation (BDL). Circulating EPCs isolated from healthy human and cirrhotic blood were characterized by flow cytometry, cultured and administered through the tail vein in BDL rats after 2 weeks of ligation. The cells were given thrice a week for 2 weeks. The untreated group of BDL rats received only saline. Fibrosis was evaluated by Masson’s trichrome staining. Dedifferentiated LSECs were identified by the expression of CD31, and activated HSCs were marked as alpha-SMA-positive cells and were studied by immunohistochemistry and western blotting in saline-, healthy EPC-, and cirrhotic EPC-treated rats. In vivo, hepatic and systemic hemodynamic parameters were evaluated. Liver functions were evaluated.ResultsIn comparison to controls, BDL rats revealed an increase of fibrosis and angiogenesis. Among the treated rats, cirrhotic EPC-treated rats had increased fibrosis grade as compared to healthy EPC-treated and saline-treated rats. There was an increase of both fibrosis and angiogenesis markers, alpha-SMA and CD31 in cirrhotic EPC-treated rats as compared to healthy EPC-treated and saline-treated rats in immunohistochemistry and western blot studies. Cirrhotic EPC-treated BDL rats had high portal pressure and portal blood flow with significantly elevated hepatic vascular resistance in comparison with healthy EPC- and saline-treated BDL animals, without significant differences in mean arterial pressure. Cirrhotic EPC-treated BDL rats also showed a substantial increase in the hepatic expression of angiogenic receptors, VEGFR2 and CXCR4 in comparison with saline-treated rats.ConclusionThe study suggests that transplantation of cirrhotic EPCs enhances LSEC differentiation and angiogenesis, activates HSCs and worsens fibrosis, thus resulting in hepatic hemodynamic derangements in BDL-induced cirrhosis.
Highlights
Angiogenesis is the process of formation of new blood vessels from pre-existing vasculature and mature endothelial cells
The percentage of CD34-vegfr2 dual positive endothelial progenitor cells (EPCs) in blood was increased in patients with cirrhosis as compared to the healthy subjects (Figure 2)
After 7 days in culture, the adherent cells stained positive for specific EPC surface proteins, vegfr2 (Figure 3F) and CD34 (Figure 3G)
Summary
Angiogenesis is the process of formation of new blood vessels from pre-existing vasculature and mature endothelial cells. Physiological angiogenesis occurs during regeneration, and pathological angiogenesis takes place during progression of fibrosis to cirrhosis and during tumorigenesis (Kaur and Anita, 2013; Gracia-Sancho et al, 2019) During both physiological and pathological angiogenesis, cellular cross-talk among several liver cell types such as sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and hepatocytes orchestrates the angiogenic response in liver. In response to tissue ischemia or traumatic injury, BM-derived EPCs are mobilized into the peripheral blood, migrate to sites of injured endothelium, and participate into endothelial differentiation and repair (Takahashi et al, 1999; Gill et al, 2001; Kawamoto et al, 2001; Balaji et al, 2013) These cells express mixed markers present on hematopoietic stem cells and mature endothelial cells such as Vegfr and CD34, but do not express CD45 (Kaur and Bajwa, 2014). This study evaluated the effect of cirrhotic and control EPCs on hepatic angiogenesis, microcirculation, and fibrosis in vivo in rat models of cirrhosis
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