Clinical-grade human liver mesenchymal stem cells for the treatment of NASH-Fibrosis through immunomodulation

Kris Gellynck, Guillaume Rommelaere, Mustapha Najimi, John Tchelingerian, Catherine Lombard, Joelle Thonnard, Giuseppe Mazza, Etienne Sokal

Background: Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic liver diseases (NAFLD), is one of the prominent liver diseases worldwide. There is currently no approved drug for the treatment of NASH and liver transplantation is the only therapeutic approach for advanced NASH. Mesenchymal stem cells (MSCs) are promising candidates to modulate the pro-inflammatory and pro-fibrogenic environment of chronic liver because of their immunomodulatory properties. HepaStem, Human adult liver-derived MSCs isolated from organs unsuitable for transplantation can be GMP-manufactured, cryopreserved and reconstituted at the bedside as an off-the-shelf product. Safety and tolerability have been shown in a phase I/II clinical trial in patients with metabolic disorders. The proposed mechanism of action in NASH is a systemic hit-and-run suppression of inflammation and stellate cell activation through the secretion of several cytokines in response to the liver inflammation.

Method: The secretion of pro-inflammatory and anti-inflammatory cytokines including HGF, IDO, PGE2 was measured using multiplexed immunoassays in cell culture with or without inflammation cocktail. The anti-inflammatory effect of HepaStem was investigated in co-culture systems with T-lymphocytes in a mixed leukocyte reaction as well as with immature and mature dendritic cells. In a preclinical high-fat model, the potency of HepaStem was compared to a vehicle, either with or without the use of immunosuppression (cyclosporine), to factor in the use of human cells in an animal model.

Results: Secretion of anti-inflammatory and anti-fibrotic cytokines was increased with the addition of an inflammatory cytokines in the culture medium HepaStem inhibited both T-lymphocyte response and the dendritic cell generation and function in co-culture experiments. In the NASH model, while the immunosuppression by itself did not affected the disease progression, cell-based treatment (3 IV injections 12.5x106 cells/kg) significantly and dose-dependently decreased collagen deposition in the pericentral region as shown by Sirius red staining. A single HepaStem injection significantly decreased the NAS score, which was mainly attributed to reduction in inflammation and thus supporting the proposed mechanism of action.  

Conclusion: Our results suggest that clinical grade liver progenitor cells have anti-fibrosis and anti-NASH effects, both in vitro and in a pre-clinical NASH model. This observation provides significant evidences to open new phase I/II studies in NASH patients as well as to apply MSCs for the treatment of chronic liver disorders.

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