Transplantation of human fetal biliary tree stem/progenitor cells into two patients with advanced liver cirrhosis

Abstract

BackgroundEfforts to identify cell sources and approaches for cell therapy of liver diseases are ongoing, taking into consideration the limits recognized for adult liver tissue and for other forms of stem cells. In the present study, we described the first procedure of via hepatic artery transplantation of human fetal biliary tree stem cells in patients with advanced cirrhosis.MethodsThe cells were immune-sorted from human fetal biliary tree by protocols in accordance with current good manufacturing practice (cGMP) and extensively characterized. Two patients with advanced liver cirrhosis (Child-Pugh C) have been submitted to the procedure and observed through a 12 months follow-up.ResultsThe resulting procedure was found absolutely safe. Immuno-suppressants were not required, and the patients did not display any adverse effects correlated with cell transplantation or suggestive of immunological complications. From a clinical point of view, both patients showed biochemical and clinical improvement during the 6 month follow-up and the second patient maintained a stable improvement for 12 months.ConclusionThis report represents proof of the concept that the human fetal biliary tree stem cells are a suitable and large source for cell therapy of liver cirrhosis. The isolation procedure can be carried out under cGMP conditions and, finally, the infusion procedure is easy and safe for the patients. This represents the basis for forthcoming controlled clinical trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s12876-014-0204-z) contains supplementary material, which is available to authorized users.

Immunohistochemical Analysis of the Stem Cell Marker Lgr5 in Pediatric Liver Disease

“…These findings are consistent with other reports that human HPC activation depends on both hepatocyte loss and decreased proliferation (13,14). Of note, similar HPC incapacitation was recently reported in liver explants from patients with severe alcoholic hepatitis compared to those with cirrhosis (28). Previous studies in rodents have also demonstrated that the regenerative capacity of cirrhotic hepatocytes can be restored if they are transplanted into healthy livers, suggesting that the microenvironment impairs effective proliferation in response to chronic injury (15)(16)(17).…”

Immune responses to bioengineered organs

“…In addition, even more primitive stem cells have been identified throughout the human biliary tree stem cells (hBTSCs) with the potential to generate hepatocytes, cholangiocytes, pancreatic islets and intestinal cells [22,47]. Independently of their donor origin, they seem to have low immunogenicity, and it is feasible to transplant them without the use of immunosuppression into human patients [48,49 ▪ ]. The lack of signs of rejection and/or allergy without any immunosuppressive treatment, seems to correlate with marginal or absence of expression of HLA classes I and II antigens both in hepatic and biliary tree stem cells from fetal liver [50–52].…”

Cell therapy in chronic liver disease

“…It has been suggested fetal liver stem cells can replace liver mass with advanced cirrhosis to a greater extent than hepatocytes (21). Human fetal biliary tree stem cells have been tested in a small number of cirrhosis patients, with clinical and biochemical improvement (22). Liver progenitor cells and the cell signaling involved in their reconstitution of liver parenchyma is still being studied, so that in the future extracellular matrix factors may be used to facilitate their induction (23).…”