Novel cells sourced for liver therapy
The Crigler-Najjar disease is a rare metabolic disorder of the liver associated with an inability to metabolise bilirubin, the by-product of haem breakdown in red blood cells. Patients present with jaundice and the only cure is liver transplantation, which however, is limited by the shortage of donors. Transplantation of genetically corrected hepatocytes has been proposed as an attractive alternative but it is hampered by the low amplification potential of these cells in vitro. Standard methods of iPSC generation induce genetic and epigenetic anomalies, which decrease the efficiency of reprogramming and re-differentiation, and may lead to long-term complications. Scientists of the EU-funded CN-I LIVER THERAPY (Potential of induced pluripotent stem cells for the treatment of Crigler-Najjar liver disease: a preclinical safety assessment) project proposed to derive liver cells from induced pluripotent stem cells (iPSC). They developed a novel method for inducing proliferative hepatic progenitor cells (iHPC) from human hepatocytes to overcome previously encountered issues. These iHPCs were obtained by culturing primary hepatocytes in dedifferentiating medium containing a cocktail of growth factors and small molecules for seven days. Transcriptome analysis revealed interesting similarities between hepatocyte reprogramming to pluripotency and dedifferentiation. However, iHPCs exhibited fewer mutations compared to iPSC generated-hepatocytes. To address the safety of iHPC transplantation, scientists injected cells into the liver of immuno-deficient mice. Results showed efficient iHPC differentiation in vivo without triggering detectable tumour development. The CN-I LIVER THERAPY team have applied for a European patent to protect the intellectual property of the method. Apart from cell therapy, these iHPC cells could be used for personalised drug testing in existing rodent animal models and in vitro assays used by pharmaceutical companies. iHPCs can be readily generated and expanded from a small number of patient cells. As such, they constitute an ideal cell source for predicting drug metabolic stability and clearance as well as liver toxicity. Furthermore, the plasticity of human hepatocytes provides a promising methodological lead for the development of a bio-artificial liver.
Keywords
Liver, Crigler-Najjar disease, CN-I LIVER THERAPY, iPSC, iHPC