Hepatic CEACAM1 Expression Indicates Donor Liver Quality and Prevents Early Transplantation Injury
Nakamura K, Kageyama S, Kaldas FM, et al. J Clin Invest. 2020;130:2689–2704.
Orthotopic liver transplantation (OLT) is accepted as the gold-standard treatment for patients with liver failure, yet it remains limited by significant donor shortage. A particular challenge is the quality of livers available for transplantation, with a large proportion of deceased donor livers not deemed to be appropriate for transplantation. It is recognized that ischemia-reperfusion injury (IRI) at the time of transplantation contributes to the development of early allograft dysfunction; however, the mechanisms underlying this process are incompletely understood.6 Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), also known as CD66a or biliary glycoprotein-1, is a transmembrane protein expressed in a number of immune and epithelial cells in which it acts as an adhesion molecule but also has a role in hepatic metabolic homeostasis. To investigate the role of CEACAM1 in IRI, Nakamura et al use a mouse model of OLT in which grafts from either wild-type or CC1−/− mice (which possess a global null mutation in CEACAM1) are subjected to extended cold storage (18 h) and subsequently transplanted into wild-type recipients.7 Mice in the CC1−/− group displayed increased evidence of IRI and higher levels of HMGB, a danger-associated molecular pattern, in addition to an enhanced infiltration with macrophages and neutrophils. The CC1−/− group also exhibited signs of injury resulting from cold storage, mediated by the ASK1/p-p38 pathway. Furthermore, preincubation of CC1−/− livers in cold storage with an ASK1 inhibitor improved outcomes.
Having established a regulatory role for CEACAM1, the authors next validated the clinical relevance in human OLT. Liver graft biopsies were obtained from 60 patients at the time of liver transplantation. These were screened for CEACAM1 as well as ASK1 and p-p38, identifying a negative correlation between CEACAM1 levels and ASK1. To test the hypothesis that pretransplantation CEACAM1 levels impact clinical outcomes, samples were clustered into high or low CEACAM1 groups based on a median of CEACAM1 levels. Samples with low levels of CEACAM1 correlated with increased liver enzymes postoperatively as well as an augmented frequency of early allograft dysfunction and poorer long-term graft function, although the latter finding did not reach statistical significance. CEACAM1 may therefore represent a useful biomarker of liver quality, as well as a point for intervention, particularly through targeting the ASK1/p-p38 pathway.
Transforming the Spleen Into a Liver-like Organ In Vivo
Wang L, Wang C, Wang Z, et al. Sci Adv. 2020;6:eaaz9974.
Regenerative medicine aims to solve several key challenges in organ transplantation—from the shortage of donor organs to the need for optimized immunosuppression. Significant progress has been made in recent years, but the field is still limited by the inability to generate the necessary vasculature to sustain the engineered tissues1. In the study from Wang et al, this limitation is addressed through a novel concept of transforming an existing organ, the spleen, to perform the function of the liver. The spleen is an ideal subject for this as it is large, has an excellent blood supply, and its absence can be tolerated well.
The authors use a mouse model to transform the spleen by remodeling the tissue and subsequently transplanting liver cells into the organ. To facilitate the necessary transformation, the spleen was initially translocated surgically to a subcutaneous location. Thereafter, the spleen was injected with soluble tumor homogenate (STH, from a sarcoma cell line) on days 7, 10, and 14 to suppress immune function and enhance the extracellular matrix. Mice injected with this homogenate demonstrated an increase in spleen size, extracellular matrix composition, and angiogenesis (probably mediated through enhanced vascular endothelial growth factor expression). Interestingly, the transformed spleens provided an immunosuppressive microenvironment, with reduced T and B cells as well as an increase in regulatory T cells.
The second step involved the transfer of liver cells into remodeled spleens (“hepatization”). Using luciferase-labeling, the authors were able to detect cells posttransplantation and demonstrated successful graft take of both allografted and xenografted human liver cells, although regular injection of STH was required to achieve this. Cessation of STH injection resulted in grafts being lost 2 wk after the last injection. Transformed spleens were able to produce albumin and metabolize drugs. Furthermore, in mice wherein 90% of the liver was removed, or wherein fulminant liver failure was induced, transformed spleens were able to take over functionality, and the mice survived.
The strategy presented offers the exciting possibility of organ repurposing thus allowing organs to be engineered from a baseline prevascularized tissue in situ, providing an advantage over more traditional decellularization-recellularization techniques.