Authors N. LANTHIER (1), N. LIN-MARQ (2), L. RUBBIA-BRANDT (2), S. CLÉMENT (2), N. GOOSSENS (1), L. SPAHR (1) / [1] University Hospitals of Geneva and Faculty of Medicine, , Switzerland, Hepato-Gastroenterology, [2] University Hospitals of Geneva and Faculty of Medicine, , Switzerland, Clinical pathology Introduction Liver stem cell therapy (SCT) is suggested as potential means to improve liver regeneration in advanced liver disease. However, data of trials and reports are heterogeneous with no systematic histological evaluation. In a recent randomized controlled trial (Spahr et al., PlosOne 2013), we observed that patients who received SCT had a similar improvement of liver function over time as compared to controls. Aim The aims of this study were firstly to specifically analyze the effect of autologous SCT on liver cell proliferation and hepatic macrophages (implicated in liver regeneration) and second to perform an in depth transcriptome analysis in paired liver biopsies before and after transarterial administration of autologous hematopoietic stem cells in patients with alcoholic hepatitis. Methods Immunohistochemistry (Ki67, CK7 and CD68), in situ hybridization (SPINK1) and global gene expression analysis were performed on liver biopsies of 58 patients (30 controls and 28 stem cell treated) both at baseline and after 4 weeks of follow-up. Results Patients who received SCT did not exhibit any increased proliferative activity in hepatocytes nor in K7 positive liver progenitor cells on the liver biopsy performed at 4 weeks compared to controls. However, on repeat biopsy, patients who received SCT showed a more important CD68+ liver macrophagic expansion as compared to controls (p<0.05). Transcriptome data revealed significant upregulated genes linked with inflammation (CD68, SAA, CXCL6), regeneration (SPINK1, HGF), fibrosis (COL1A1) and stem cells (CD45) in SCT patients compared to controls. No major changes in gene pathways involved in liver growth, and in particular in cell cycle proteins were evidenced between the two groups. SPINK1 mRNA identified as a good baseline prognostic factor (Lanthier et al., J Hepatol 2015) was present by in situ hybridization at week 4 in SCT patients in liver parenchyma areas adjacent to macrophage recruitment and liver cell proliferation. Conclusions The analysis of liver tissue after SCT demonstrated an expansion of macrophages concurrent with an upregulated expression of genes involved in inflammatory and regenerative pathways. With the negative results of the clinical trial, it has to be interpreted as a weak impact of the SCT, which is not able to modify the clinical course of this severe liver disease.
