Early cirrhosis and a preserved bone marrow niche favour regenerative response to growth factors in decompensated cirrhosis

Abstract

Background: Exogenous growth factor-mobilized bone marrow (BM) stem cells have shown a differential response in the management of decompensated cirrhosis (DC). This study was designed to evaluate potential clinical benefit of adding Erythropoietin (EPO) in granulocyte-colony stimulating factor (G-CSF)-mobilized stem cell therapy, possible mechanisms of regeneration and predictive factors of regenerative response. Methods: Sixty consecutive DC patients received either G-CSF with EPO (Group A; n = 30) or G-CSF and placebo (Group B; n = 30) for 2 months and were carefully followed up for 1 year. Baseline and post-treatment liver biopsy, BM biopsy and BM aspirate were analysed for fibro-inflammatory and regenerative response and BM hematopoietic reservoir. Results: Addition of EPO to G-CSF showed a significant improvement in Child-Pugh score (P = 0.03) and MELD score (P = 0.003) as compared to G-CSF alone, with reduction in mortality (16.6% vs 36.7%, P = 0.09). The combination arm also demonstrated a decreased incidence of acute kidney injury (P < 0.001), encephalopathy (P = 0.005) and refilling of ascites (P = 0.03). Compared to monotherapy, it increased CD163+ macrophages (P = 0.013), Ki67+ index (P < 0.001) with decrease in α-SMA levels (P < 0.001) in liver tissue. The response was better with grade 1 and 2 than with grade 3 ascites; Child B cirrhosis and MELD < 16. Non-responders had lower hematopoietic stem cells (HSCs) at baseline. On multivariate analysis, the liver disease severity (MELD < 16) and a relatively preserved BM (BM-HSCs > 0.4) predicted therapeutic response (AUROC = 0.82). Conclusions: Early DC (MELD < 16) patients with mild-moderate ascites and those with a healthy cellular baseline BM respond better to growth factor therapy. Addition of EPO to G-CSF provides better regenerative response than G-CSF monotherapy.