Transplantation of human stem cell-derived hepatocytes in an animal model of acute liver failure

Ramanathan, R. K.; Pettinato, Giuseppe; Lee, David D.; Wen, Xuejun; Mangino, Martin J.; Fisher, Robert A.

doi:10.1016/j.surg.2015.04.014

Cited by 13 publications

(14 citation statements)

References 26 publications

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“…8A). 36,37 Sham operation was performed as control (n = 6). At 4 weeks after transplantation, we identified biliary duct-like structures that stained positive for hCK19 (Fig.…”

Section: Potential Of Hbo For In Vivo Usementioning

confidence: 99%

Generation of hepatobiliary organoids from human induced pluripotent stem cells

Ren

et al. 2019

Journal of Hepatology

179

145

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“…8A). 36,37 Sham operation was performed as control (n = 6). At 4 weeks after transplantation, we identified biliary duct-like structures that stained positive for hCK19 (Fig.…”

Section: Potential Of Hbo For In Vivo Usementioning

confidence: 99%

Generation of hepatobiliary organoids from human induced pluripotent stem cells

Ren

et al. 2019

Journal of Hepatology

179

145

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“…The incorporation of hECs with hiPSCs within hEBs could provide a sustained hepatocyte function in vivo . We previously explored the use of hECs interlaced with hiPSCs to ameliorate the challenges of engraftment of the transplanted cells 33 . The ability of hECs to secrete endogenous angiogenic factors, which might aid in recruiting new blood vessels to the transplantation site, has been described 34–36 .…”

Section: Introductionmentioning

confidence: 99%

Generation of fully functional hepatocyte-like organoids from human induced pluripotent stem cells mixed with Endothelial Cells

Pettinato

Lehoux

Ramanathan

et al. 2019

Sci Rep

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125

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Despite advances in stem cell research, cell transplantation therapy for liver failure is impeded by a shortage of human primary hepatocytes (HPH), along with current differentiation protocol limitations. Several studies have examined the concept of co-culture of human induced pluripotent cells (hiPSCs) with various types of supporting non-parenchymal cells to attain a higher differentiation yield and to improve hepatocyte-like cell functions both in vitro and in vivo . Co-culturing hiPSCs with human endothelial cells (hECs) is a relatively new technique that requires more detailed studies. Using our 3D human embryoid bodies (hEBs) formation technology, we interlaced Human Adipose Microvascular Endothelial Cells (HAMEC) with hiPSCs, leading to a higher differentiation yield and notable improvements across a wide range of hepatic functions. We conducted a comprehensive gene and protein secretion analysis of our HLCs coagulation factors profile, showing promising results in comparison with HPH. Furthermore, a stage-specific glycomic analysis revealed that the differentiated hepatocyte-like clusters (HLCs) resemble the glycan features of a mature tissue rather than cells in culture. We tested our HLCs in animal models, where the presence of HAMEC in the clusters showed a consistently better performance compared to the hiPSCs only group in regard to persistent albumin secretion post-transplantation.

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“…However, in vivo transplantation of differentiated hepatocytes from DPSCs shows significant improvement on both acute liver injury and secondary biliary cirrhosis 20 . The remarkable liver protection property and regeneration potential of damaged liver tissues after in vivo administration of differentiated hepatocytes from various stem cells has been demonstrated 1 , 36 , 37 . Moreover, to generate tissue-engineered total or partial liver organ that could replace the liver transplantation, well-organized and highly effective in vitro hepatocyte differentiation protocol from stem cells is necessary.…”

Section: Discussionmentioning

confidence: 99%

Stem Cells from Cryopreserved Human Dental Pulp Tissues Sequentially Differentiate into Definitive Endoderm and Hepatocyte-Like Cells in vitro

et al. 2017

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We previously described a novel tissue cryopreservation protocol to enable the safe preservation of various autologous stem cell sources. The present study characterized the stem cells derived from long-term cryopreserved dental pulp tissues (hDPSCs-cryo) and analyzed their differentiation into definitive endoderm (DE) and hepatocyte-like cells (HLCs) in vitro. Human dental pulp tissues from extracted wisdom teeth were cryopreserved as per a slow freezing tissue cryopreservation protocol for at least a year. Characteristics of hDPSCs-cryo were compared to those of stem cells from fresh dental pulps (hDPSCs-fresh). hDPSCs-cryo were differentiated into DE cells in vitro with Activin A as per the Wnt3a protocol for 6 days. These cells were further differentiated into HLCs in the presence of growth factors until day 30. hDPSCs-fresh and hDPSCs-cryo displayed similar cell growth morphology, cell proliferation rates, and mesenchymal stem cell character. During differentiation into DE and HLCs in vitro, the cells flattened and became polygonal in shape, and finally adopted a hepatocyte-like shape. The differentiated DE cells at day 6 and HLCs at day 30 displayed significantly increased DE- and hepatocyte-specific markers at the mRNA and protein level, respectively. In addition, the differentiated HLCs showed detoxification and glycogen storage capacities, indicating they could share multiple functions with real hepatocytes. These data conclusively show that hPDSCs-cryo derived from long-term cryopreserved dental pulp tissues can be successfully differentiated into DE and functional hepatocytes in vitro. Thus, preservation of dental tissues could provide a valuable source of autologous stem cells for tissue engineering.

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Transplantation of human stem cell-derived hepatocytes in an animal model of acute liver failure

Cited by 13 publications

References 26 publications

Generation of hepatobiliary organoids from human induced pluripotent stem cells

Generation of hepatobiliary organoids from human induced pluripotent stem cells

Generation of fully functional hepatocyte-like organoids from human induced pluripotent stem cells mixed with Endothelial Cells

Stem Cells from Cryopreserved Human Dental Pulp Tissues Sequentially Differentiate into Definitive Endoderm and Hepatocyte-Like Cells in vitro

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