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

Abstract

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. Sixty consecutive DC patients received either G-CSF with EPO (Group A; n=30) or G-CSF and placebo (Group B; n=30) for 2months and were carefully followed up for 1year. Baseline and post-treatment liver biopsy, BM biopsy and BM aspirate were analysed for fibro-inflammatory and regenerative response and BM hematopoietic reservoir. 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). 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.