Rescue of Lethal Hepatic Failure by Hepatized Lymph Nodes in Mice

Abstract

BACKGROUND & AIMS Hepatocyte transplantation is a potential therapeutic approach for liver disease. However, most patients with chronic hepatic damage have cirrhosis and fibrosis, which limit the potential for cell-based therapy of the liver. The development of an ectopic liver as an additional site of hepatic function represents a new approach for patients with an end-stage liver disease. We investigated the development and function of liver tissue in lymph nodes in mice with liver failure. METHODS Hepatocytes were isolated from 8 to 12-week-old mice and transplanted by intraperitoneal injection into 8- to 12-week-old Fah-/- mice, a model of the human liver disease tyrosinemia type I. Survival was monitored and the locations and functions of the engrafted liver cells were determined. RESULTS Lymph nodes of Fah-/- mice were colonized by transplanted hepatocytes; Fah+ hepatocytes were detected adjacent to the CD45+ lymphoid cells of the lymphatic system. Ten weeks after transplantation, these mice had substantial improvements in serum levels of transaminases, bilirubin, and amino acids. Homeostatic expansion of donor hepatocytes in lymph nodes rescued the mice from lethal hepatic failure. CONCLUSIONS Functional ectopic liver tissue in lymph nodes rescues mice from lethal hepatic disease; lymph nodes might therefore be used as sites for hepatocyte transplantation.

The Lymph Node as a New Site for Kidney Organogenesis

“…Thus, the LN can be exploited to study the behavior of multiple cell populations with stem/progenitor features. In conclusion, our previous and current findings suggest that LNs can have multiple applications, including restoration of tissue function [20,21], drug testing [22], developmental studies, disease modeling, and cell fate tracking (Fig. 7D).…”

“…Therefore, it will be essential to provide the reprogrammed cells with a suitable niche; otherwise the newly established phenotype will be unstable. Our previous [20][21][22] and current studies indicate the LNs might meet this demand. When embryonic kidney fragments were transplanted into the LNs, host blood vessels integrated into the developing glomeruli suggesting access to the bloodstream, a critical challenge to achieve filtration.…”

“…Importantly, new angiogenesis occurs fast enough in this site to sustain cell survival and engraftment. All these characteristics allowed us to generate functional liver, thymus, and pancreatic islets within the mouse LN [20,21].…”

Toward a blueprint for regeneration

“…Gufa Lin (University of Minnesota, USA) showed how a graft of regeneration-competent cells supplemented by a slow-release cocktail of factors, including Shh, Fgf10 and Thymosin Beta-4, could enhance the regeneration of amputated adult Xenopus limbs, which normally would only form a cartilage spike. Eric Lagasse (University of Pittsburgh, USA) is interested in cell therapies that provide function from ectopic sites, and has found promise in lymph nodes (Hoppo et al, 2011). He described how they have been able to transplant hepatocytes, pancreatic beta cell islets, and thymocytes into mouse lymph nodes, where these tissues grow, become vascularized and can serve functions of host organs.…”

Humanized mice with ectopic artificial liver tissues

“…Use of partial hepatectomy with portal-caval shunt has been shown to improve hepatocyte engraftment and function in allogenic rat models (19,20), suggesting that transplanted hepatocytes depend on signals (hepatotrophic factors) circulating from the portal vein. Despite these findings, support of implanted hepatocytes by sequential delivery of seeded cells, growth factors, hormones, and/or proangiogenic molecules has had limited success (21)(22)(23)(24), and recent evidence showing promise for the survival of hepatocytes transplanted in the ectopic lymph node remains dependent on mouse liver injury (25). We hypothesized that an integrated system, based on hepatocyte encapsulation and the incorporation of juxtacrine and paracrine signals to stabilize the cell phenotype before, rather than during/after transplantation, could mitigate the requirement for portal venous flow or liver injury in vivo.…”