Autologous macrophage therapy promotes stem cell-mediated liver regeneration:a novel therapy for end-stage liver disease

Liver disease is the 5th commonest cause of death in the UK and deaths from cirrhosis are rapidly rising. Currently the only curative option for end-stage liver disease is liver transplantation and this is limited in availability due to a lack of suitable donor livers. As a result of this, many patients die whilst waiting for a donor organ, hence new therapeutic strategies for patients with end-stage liver disease are urgently required. Cell therapy using bone marrow has been tested in rodents and has shown to significantly reduce liver scarring, which is a precursor to cirrhosis. We have found that in addition this effect bone marrow therapy stimulates the livers own stem cells to start dividing and regenerate the liver. We have identified the cell type within the bone marrow that is responsible for this effect termed macrophages. This is exciting as these cells can be isolated from a patient?s blood in an immature form in large numbers and matured in the laboratory effectively.
Here, we describe a novel approach to the treatment of liver cirrhosis using blood derived cells which have been matured outwith the body into macrophages prior to re-injection into the blood stream. This therapy is simple to administer and has the potential to reduce liver scarring and promote liver regeneration. The pre-clinical studies are designed to test the safety and effectiveness of this technique in a wide range of liver disease models- if they are effective they will be directly translated into patients in a clinical pilot study.

Liver disease is the 5th commonest cause of death in the UK and deaths from cirrhosis are rapidly rising. Currently the only curative option for end-stage liver disease is liver transplantation and this is limited in availability due to a lack of suitable donor organs. Many patients die whilst waiting for a donor organ, hence new therapeutic strategies for patients with end-stage chronic liver disease are urgently required.

Autologous bone marrow (BM) cell therapy has been tested in rodent models and has been shown to significantly reduce liver fibrosis. Interestingly, from our studies we have found that in addition to the anti-fibrogenic effect, BM cell therapy also activates the adult liver?s stem cell pool, producing a classic liver progenitor cell (LPC) reaction in the host. This is of considerable interest, as LPCs are known to facilitate liver regeneration in situations in which adult hepatocytes are unable to. Our studies indicate that is the BM-derived macrophages that are the effector cells in this response. Furthermore, we have recently found that na?ve macrophages, matured ex vivo in low adherence culture conditions are as effective as whole BM in eliciting both anti-fibrotic and pro-regenerative effect. Thus macrophage therapy may elicit the dual beneficial effects of reducing fibrosis and regenerating liver from its endogenous stem cell pool. This proposal aims to develop a GMP-compatible system for maturation of monocytes into macrophages using MCSF and low adhesion culture conditions. We will then define the optimal form of LPC-promoting macrophage therapy and rigorously test its safety in a comprehensive series of animal models and explore the mechanism by which macrophage therapy promotes LPC mediated liver regeneration. Using this information we will validate the maturation system for human monocytes and test them in vivo in an immunodeficient mouse (NOG) liver injury model. If pre-clinical studies demonstrate that macrophage therapy is safe and effectively promotes liver regeneration then we will have achieved our milestone to allow us to progress to a clinical study. The clinical study will involve using autologous monocytes, matured ex-vivo into macrophages delivered to suitable patients (as determined by our animal models) with liver cirrhosis. Measured outcomes will include markers of liver function, liver regeneration and liver fibrosis.