Immunogenicity and Immunomodulatory Properties of Hepatocyte-like Cells Derived from Human Amniotic Epithelial Cells

Abstract

Hepatocyte transplantation is being trialled as an alternative to whole organ transplant for patients with acute liver failure and liver specific metabolic diseases. Due to the scarcity of human hepatocytes, hepatocyte-like cells (HLC) generated from stem cells may become a viable alternative to hepatocyte transplantation. Human amniotic epithelial cells (hAEC) from the placenta have stem cell-like properties and can be differentiated into HLC. Naïve hAEC have low immunogenicity and exert immunomodulatory effects that may facilitate allogeneic transplantation. However, whether the immunogenicity and immunomodulatory properties alter with differentiation into HLC are unknown. We further characterized HLC generated from hAEC, examined changes in human leucocyte antigens (HLA) and co-stimulatory molecules and effects exerted by the HLC on human peripheral blood mononuclear cells (PBMC). HLC derived from hAEC expressed proteins found in hepatocytes, had CYP3A4 drug metabolizing enzyme activity and secreted urea. IFN-γ treatment increased HLA Class IA, Class II and co-stimulatory molecule CD40 expression in the HLC. IFN-γ treated HLC stimulated proliferation of PBMC in one-way mixed lymphocyte reactions and were more immunogenic than undifferentiated hAEC. However, the HLC showed immunomodulatory properties and inhibited mitogen induced PBMC proliferation in vitro. PBMC proliferation may have been inhibited by IL-6, TGF-β1, PGE2 and HLA-G secreted by the HLC. The retention of immunomodulatory properties may enable HLC grafts to survive for longer periods despite the immunogenicity of the HLC.

Osteodifferentiated Mesenchymal Stem Cells from Bone Marrow and Adipose Tissue Express HLA-G and Display Immunomodulatory Properties in HLA-Mismatched Settings: Implications in Bone Repair Therapy

“…For instance, human amniotic epithelial cells, which have stem cell-like properties, retain their immunosuppressive functions after differentiation into hepatocyte-like cells [20]. Also, human Wharton's jelly-derived MSCs maintain the expression of immunomodulatory molecules, such as HLA-G, when subjected to osteogenic differentiation in vitro [21].…”

Proliferation and survival of human amniotic epithelial cells during their hepatic differentiation

“…Replacing hepatocytes with hepatocyte-like cells generated from stem cells is an alternative strategy to overcome the shortage of hepatocytes. Naive hAECs display some relevant features of hepatic progenitors and some characteristic expression of mature hepatocyte markers [ 21 , 75 ], making amniotic cells attractive as stem cells source for hepatocyte-like cells production. Many studies have focused their efforts on the regenerative properties and differentiation potential of human amniotic membrane stem cells [ 18 , 31 , 36 , 60 , 76 , 77 ], yet, information concerning hAECs biology and/or their hepatic differentiation is rare.…”

Therapeutic efficiency of human amniotic epithelial stem cell-derived functional hepatocyte-like cells in mice with acute hepatic failure

“…The placental tissue is a medical waste after birth, and large quantities of hAESCs can be easily obtained from the donor’s amnion and cultured in vitro without ethical and legal issues. In addition, hAESCs have broader differentiation potential and can differentiate into all three germ layers: ectoderm (neural cells) [ 23 , 30 ], mesoderm (cardiomyocyte) [ 31 ], and endoderm (liver [ 23 , 32 , 33 ] and pancreas [ 23 , 34 – 36 ]) in vitro. Furthermore, hAESCs have low immunogenicity and no tumorigenicity [ 37 ].…”

“…Recently, several investigators have described the differentiation of hAESCs into cells that display hepatic characteristics. Yang et al observed that human amniotic epithelial cells can be differentiated into hepatocyte-like cell, which expressed hepatocyte-specific proteins ALB and CYP3A4 [ 33 ]. Fabio et al found that HLCs derived from hAESCs expressed hepatocyte markers at levels comparable to those of fetal hepatocytes [ 32 ].…”