Enhanced liver progenitor cell survival and differentiation in vivo by spheroid implantation in a vascularized tissue engineering chamber
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2013-05-01
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Biomaterials
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ELSEVIER SCI LTD
Melbourne Authors
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Surgery (St Vincent's)
Paediatrics (RCH)
Nursing
Paediatrics (RCH)
Nursing
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Journal Article
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Yap, K. K., Dingle, A. M., Palmer, J. A., Dhillon, R. S., Lokmic, Z., Penington, A. J., Yeoh, G. C., Morrison, W. A. & Mitchell, G. M. (2013). Enhanced liver progenitor cell survival and differentiation in vivo by spheroid implantation in a vascularized tissue engineering chamber. Biomaterials, 34 (16), pp.3992-4001. https://doi.org/10.1016/j.biomaterials.2013.02.011.
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Abstract
Liver tissue engineering is hampered by poor implanted cell survival due to inadequate vascularization and cell-cell/cell-matrix interactions. Here, we use liver progenitor cell (LPC) spheroids to enhance cell-cell/cell-matrix interactions, with implantation into an angiogenic in vivo mouse chamber. Spheroids were generated in vitro in methylcellulose medium. Day 2 spheroids were optimal for implantation (22,407 +/-645 cells/spheroid), demonstrating maximal proliferation (Ki67 immunolabeling) and minimal apoptosis (caspase-3 immunolabelling). In vivo chambers established bilaterally on epigastric vessels of immunodeficient mice were implanted with equivalent numbers of LPCs as a cell suspension (200,000 cells), or spheroids (9 spheroids). At day 14, a trend of increased LPC survival was observed in spheroid-implanted chambers [pan-cytokeratin (panCK+) cells, p = 0.38, 2.4 fold increase)], with significantly increased differentiation [cytokeratin 18 (CK18+) cells, p < 0.002, 5.1 fold increase)] compared to cell suspension-implanted chambers. At day 45, both measures were significantly increased in spheroid-implanted chambers (panCK, p < 0.006, 16 fold increase) (CK18, p < 0.019, 6 fold increase). Hepatic acini/plates of CK18 + cells expressed hepatocyte nuclear factor 4-α and β-catenin, indicating ongoing hepatic differentiation. Spheroid cell-delivery significantly increased LPC survival and differentiation compared to conventional cell suspensions. This LPC spheroid/vascularized chamber model has clinical potential to generate three-dimensional vascularized liver tissue for liver replacement.