Cord-blood-PRP attenuates fibrogenic features of TGFβ-activated hepatic stellate cells in in vitro and animal models.

Chronic liver fibrosis is a progressive and globally prevalent pathological condition that poses a substantial threat to human health, frequently culminating in cirrhosis and hepatocellular carcinoma (HCC). A range of etiological factors, including metabolic disorders such as diabetes and obesity, chronic alcohol consumption, prolonged medication use, and exposure to hepatotoxic agents, contribute to the rising incidence and persistence of this disease. Despite considerable progress in therapeutic development, effective curative interventions remain limited, underscoring the need for novel regenerative strategies. Recent investigations have highlighted the regenerative and anti-inflammatory potential of umbilical cord blood-derived platelet-rich plasma (UCB-PRP), suggesting its capacity to modulate tissue repair mechanisms. Building on these findings, the present study was designed to evaluate the effects of UCB-PRP on the fibrogenic activity of transforming growth factor-β (TGFβ)-activated human hepatic stellate cells (LX2). Through this approach, we sought to elucidate whether UCB-PRP exerts a modulatory influence on hepatic stellate cell activation and extracellular matrix remodeling, key events in the pathogenesis of liver fibrosis. The in vitro component of this study examined the influence of UCB-PRP treatment on gene expression, protein expression, and functional characteristics of TGFβ-activated LX2 cells (aLX2). Complementarily, the in vivo phase assessed the impact of UCB-PRP administration on hepatic function and histopathological alterations in a murine model of liver fibrosis. Exposure of aLX2 cells to UCB-PRP resulted in a marked downregulation of fibrosis-associated genes, including COL1A1(∼ 0.3-fold, p ≤ 0.01), MMP2(∼ 0.2-fold, p ≤ 0.05), and XBP1, (∼ 0.4-fold, p ≤ 0.05) as well as corresponding reductions in the expression of key fibrogenic proteins such as GLI2, XBP1, TGFβ (3 ng/ml reduction per 10 k cells,p ≤ 0.0001), collagen)1.5 ng/ml reduction per 10 k cells,p ≤ 0.0001 (, and fibronectin (2.5 ng/ml reduction per 10 k cells,p ≤ 0.0001). These molecular changes were accompanied by a substantial attenuation of fibrogenic cellular behaviors, including decreased migratory activity (∼ 40%, p ≤ 0.0001) and distinct alterations in cell phenotype. In vivo, UCB-PRP administration in fibrotic mice led to notable improvements in liver function tests, reflected by decreased serum levels of alanine aminotransferase (ALT) (∼ 50 U/L,p ≤ 0.05), aspartate aminotransferase (AST) (∼ 40 U/L,p ≤ 0.05), and total bilirubin (∼ 3 mg/dL), alongside histopathological evidence of hepatic recovery. Treated tissues exhibited reduced inflammatory cell infiltration and enhanced structural repair, indicating accelerated tissue regeneration. Collectively, these findings demonstrate that UCB-PRP attenuates liver fibrogenesis by suppressing TGFβ-driven HSC activation and interfering with Hedgehog, GLI2 and ER stress, XBP1 signaling convergence. By simultaneously targeting inflammatory and fibrogenic pathways, UCB-PRP represents a promising mechanism-based regenerative strategy and a potential adjunct candidate for future antifibrotic combination therapies, warranting advanced preclinical validation and clinical translation. These findings underscore the clinical relevance of UCB-PRP as a multifaceted therapeutic agent for liver fibrosis. UCB-PRP is enriched with bioactive components such as vascular endothelial growth factor A (VEGF-A), tissue inhibitor of metalloproteinases-2 (TIMP-2), and catalase, which are known to promote tissue regeneration and exhibit anti-fibrotic properties. Notably, UCB-PRP has been shown to suppress hepatic stellate cell activation and reduce collagen deposition, key processes in the pathogenesis of liver fibrosis. Given its low immunogenicity and abundance of regenerative factors, UCB-PRP holds promise as a safe and effective therapeutic option. These attributes support the advancement of UCB-PRP into clinical trials aimed at evaluating its efficacy and safety in treating chronic liver diseases.