Hepatic stellate cells improve engraftment of human primary hepatocytes: A pre-clinical transplantation study in animal model.
(2015) Cell Transplantation — Vol. 24, n° 12, p. 2557-2571 (2015)
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- Human hepatocytes are used for liver cell therapy, but the small number of engrafting cells limits the benefit of cell transplantation. We tested whether co-transplantation of hepatocytes with hepatic stellate cells (HSC) could improve hepatocyte engraftment in vivo. Human primary hepatocytes were transplanted into SCID mice either alone or in a mixture with HSC (quiescent or after culture-activation) or LX-2 cells (ratio 20:1). Four weeks after transplantation into mouse livers, human albumin positive (huAlb(+)) hepatocytes were found scattered. When co-transplanted in a mixture with HSC or LX-2 cells, huAlb(+) hepatocytes formed clusters and were more numerous occupying 2 to 5.9-fold more surface on the tissue section than in livers transplanted with hepatocytes alone. Increased huAlb mRNA expression in livers transplanted with the cell mixtures confirmed those results. The presence of HSC increased the number of hepatocytes entrapped in the host liver at an early time point post-transplantation but not their proliferation in situ as assessed by cumulative incorporation of BrdU. Importantly, 4 weeks post-transplantation, we found no accumulation of αSMA(+) activated HSC or collagen deposition. To follow the fate of transplanted HSC, HSC derived from GFP(+) mice were injected into GFP(-) littermate: 17 hours post-transplant, GFP(+) HSC were found in the sinusoids, without proliferating or actively producing ECM; they were undetectable at later time points. Co-culture with HSC improved the number of adherent hepatocytes, with best attachment obtained when hepatocytes were seeded in contact with activated HSC. In vivo, co-transplantation of hepatocytes with HSC into a healthy liver recipient does not generate fibrosis but significantly improves the engraftment of hepatocytes, probably by ameliorating cell homing.
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Dusabineza, A.-C., Najimi, M., Van Hul, N., Legry, V., Khuu, N. D., van Grunsven, L. A., Sokal, E., & Leclercq, I. (2015). Hepatic stellate cells improve engraftment of human primary hepatocytes: A pre-clinical transplantation study in animal model. Cell Transplantation, 24(12), 2557-2571. https://doi.org/10.3727/096368915X686788 (Original work published 2015)