Fat‐associated lymphoid clusters as expandable niches for ectopic liver development

Abstract

Background and Aims Hepatocyte transplantation holds great promise as an alternative approach to whole‐organ transplantation. Intraportal and intrasplenic cell infusions are primary hepatocyte transplantation delivery routes for this procedure. However, patients with severe liver diseases often have disrupted liver and spleen architectures, which introduce risks in the engraftment process. We previously demonstrated i.p. injection of hepatocytes as an alternative route of delivery that could benefit this subpopulation of patients, particularly if less invasive and low‐risk procedures are required; and we have established that lymph nodes may serve as extrahepatic sites for hepatocyte engraftment. However, whether other niches in the abdominal cavity support the survival and proliferation of the transplanted hepatocytes remains unclear. Approach and Results Here, we showed that hepatocytes transplanted by i.p. injection engraft and generate ectopic liver tissues in fat‐associated lymphoid clusters (FALCs), which are adipose tissue–embedded, tertiary lymphoid structures localized throughout the peritoneal cavity. The FALC‐engrafted hepatocytes formed functional ectopic livers that rescued tyrosinemic mice from liver failure. Consistently, analyses of ectopic and native liver transcriptomes revealed a selective ectopic compensatory gene expression of hepatic function–controlling genes in ectopic livers, implying a regulated functional integration between the two livers. The lack of FALCs in the abdominal cavity of immunodeficient tyrosinemic mice hindered ectopic liver development, whereas the restoration of FALC formation through bone marrow transplantation restored ectopic liver development in these mice. Accordingly, induced abdominal inflammation increased FALC numbers, which improved hepatocyte engraftment and accelerated the recovery of tyrosinemic mice from liver failure. Conclusions Abdominal FALCs are essential extrahepatic sites for hepatocyte engraftment after i.p. transplantation and, as such, represent an easy‐to‐access and expandable niche for ectopic liver regeneration when adequate growth stimulus is present.

Intercellular communication in peritoneal dialysis

“…Fat-associated lymphoid clusters (FALCs) are a unique anatomical structure of the peritoneum, specifically localized in the omentum. FALCs are identified leukocyte aggregates, mainly composed of B and T lymphocytes and stromal cells, designed to maintain peritoneal homeostasis and mitigate local inflammation ( Han et al, 2022 ). These clusters of leukocytes possess the unique capacity to collect fluids, particles, and cells from the peritoneal cavity ( Buscher et al, 2016 ; Cruz-Migoni and Caamano, 2016 ; Liu M. et al, 2021 ; Terri et al, 2021 ).…”

3D Printing of a Vascularized Mini‐Liver Based on the Size‐Dependent Functional Enhancements of Cell Spheroids for Rescue of Liver Failure

“…Due to the low cell survival in the harsh local microenvironment, we and others have previously shown that ectopically implanted liver mimics could increase the survival ratio of ALF-challenged animal models, ameliorate oxidative stress and inflammation, and herein advance liver regeneration. [10,12] Therefore, in this study we first subcutaneously implanted the biomimetic hepatic analogs near the inguinal fat pads with rich blood vessels to study their therapeutic efficacy in the treatment of CCl 4 -induced ALF (Figure 8a).…”

Fat‐associated lymphoid clusters: Supporting visceral adipose tissue B cell function in immunity and metabolism

“…Expansion of the number and size of FALCs could offer important therapeutic oportunities in the field of hepatocyte or islet transplantation into the omentum. [70][71][72] Hepatocyte engraftment in the omentum can be increased by inducing peritoneal inflammation to expand available FALCs for ectopic liver regeneration, 70…”

“…How cross talk between inflammatory signals and stromal cells fine‐tune the number and function of FALCs is probably context dependent and remains to be elucidated. Expansion of the number and size of FALCs could offer important therapeutic oportunities in the field of hepatocyte or islet transplantation into the omentum 70–72 . Hepatocyte engraftment in the omentum can be increased by inducing peritoneal inflammation to expand available FALCs for ectopic liver regeneration, 70 demonstrating the relevance of the approach but highlighting the need to identify factors promoting FALC niche expansion without inducing acute inflammation.…”