Abstract
BackgroundLiver stem cell therapy (SCT) has been suggested as a promising means to improve liver regeneration in advanced liver disease. However, data from trials are heterogeneous, with no systematic histological evaluation. The aim of this study is to specifically analyze the effect of autologous SCT on liver regeneration and on gene expression changes.MethodsIndividuals in the randomized controlled trial of SCT in alcoholic hepatitis with paired liver biopsies were included (n = 58). Immunohistochemistry (Ki67, K7, and CD68), in situ hybridization (SPINK1), and global gene expression analysis were performed on liver biopsies (30 control patients and 28 patients with transarterial administration of bone marrow-derived stem cells) both at baseline and after 4 weeks of follow-up.ResultsNo difference between the two groups could be observed regarding the proliferative hepatocyte number, proliferative K7-positive cells, or total K7-positive cells at the 4-week follow-up liver biopsy. However, patients who received SCT showed a more important liver macrophagic expansion as compared to standard treatment. Transcriptome data revealed changes in genes linked with inflammation (CD68 and SAA), regeneration (SPINK1 and HGF), fibrosis (COL1A1), and stem cells (CD45). No changes in gene pathways involved in liver growth and cell cycle proteins were evident. SPINK1 mRNA was present by in situ hybridization at week 4 in SCT patients in the liver parenchyma areas adjacent to macrophage recruitment and liver cell proliferation.ConclusionsThe 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 from the clinical trial, the impact of the SCT has to be interpreted as weak, and it is not able to modify the clinical course of this severe liver disease.
Highlights
Liver stem cell therapy (SCT) has been suggested as a promising means to improve liver regeneration in advanced liver disease
In a recent randomized controlled trial [8], identified as a high-quality study [6], we investigated the effect of autologous bone marrow stem cell transplantation (SCT) in alcoholic hepatitis (AH) and explored the evolution of histological alterations during follow-up using a repeat liver biopsy at 4 weeks
Hepatocyte (Hep) proliferation decreased between week 0 and week 4, not significantly, and was similar between SCT patients and controls (Fig. 1a and b)
Summary
Liver stem cell therapy (SCT) has been suggested as a promising means to improve liver regeneration in advanced liver disease. Limitations of clinical trials that aimed to explore the effect of granulocyte-colony stimulating factors (GCSF) [2, 3] and/or stem cell transplantation [4, 5] include lack of power due to the small sample size and major heterogeneity in the protocol design (including absence of systematic liver biopsy), disease etiologies, endpoints, methods of stem cell collection (from the bone marrow or from the blood, with or without cell mobilization by GCSF), cell infusion number, and route of administration The results of those investigations are summarized in two recent reviews [6, 7]. Systematic investigations of SCT in AH (controlled and histologically based) are of great importance with regards to the heterogeneity of the disease, the role of alcohol abstinence, and the possible impact on specific pathways
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