Lygenesis is the company founded to conduct the clinical development of research into the use of lymph nodes to support the growth and function of organoids. Lymph nodes are found in the lymphatic system, places where immune cells can coordinate with one another in order to produce an immune response. Mammals have more lymph nodes than they need, and so it is possible to insert small pieces of organ tissue into a few lymph nodes, transforming them into miniature organs, without harming the immune system. This can in principle work well for factory organs like the liver and thymus, which carry out functions that do not have a strong dependency on structure or location in the body.
The primary thrust of the work at Lygenesis is to provide a way to support failing liver function, but the company intends to do the same for the thymus. The latter is perhaps more interesting a line of work, given that loss of thymus tissue occurs early in life, and the thymus is responsible for the maturation of T cells of the adaptive immune system. Thymic atrophy is an important contributing factor in the age-related loss of immune function, as the supply of replacement immune cells diminishes over time. Today’s news is focused on the liver, however. Here, researchers show that their approach works in a large animal model, specifically pigs.
The cells of the liver normally replenish themselves, but need a healthy, nurturing environment to regenerate. However, in end-stage liver disease, the liver is bound up by scar tissue and too toxic for the cells to make a comeback. Nearly a decade ago, researchers noticed that if they injected healthy liver cells into the lymph nodes of a mouse, they would flourish, forming an auxiliary liver to take over the tasks of the animals’ genetically induced malfunctioning liver. But mice are small. Researchers needed to show that a large animal could grow a meaningful mass of secondary liver tissue to overcome liver disease.
To mimic human liver disease in pigs, the researchers diverted the main blood supply from the liver, and at the same time, they removed a piece of healthy liver tissue and extracted the hepatocytes. Those liver cells were then injected into the abdominal lymph nodes of the same animal they came from. All six pigs showed a recovery of liver function, and close examination of their lymph nodes revealed not only thriving hepatocytes, but also a network of bile ducts and vasculature that spontaneously formed among the transplanted liver cells. The auxiliary livers grew bigger when the damaged tissue in the animals’ native liver was more severe, indicating that the animals’ bodies are maintaining an equilibrium of liver mass, rather than having runaway growth akin to cancer.
Orthotopic liver transplantation continues to be the only effective therapy for patients with end-stage liver disease. Unfortunately, many of these patients are not considered transplant candidates, lacking effective therapeutic options that would address both the irreversible progression of their hepatic failure and the control of their portal hypertension. In this prospective study, a swine model was exploited to induce sub-acute liver failure. Autologous hepatocytes, isolated from the left hepatic lobe, were transplanted into the mesenteric lymph nodes by direct cell injection.
30 to 60 days after transplantation, hepatocyte engraftment in lymph nodes was successfully identified in all transplanted animals with the degree of ectopic liver mass detected being proportional to the induced native liver injury. These ectopic livers developed within the lymph nodes showed remarkable histologic features of swine hepatic lobules, including the formation of sinusoids and bile ducts. Based on our previous mouse model and the present pig models of induced sub-acute liver failure, the generation of auxiliary liver tissue using the lymph nodes as hepatocyte engraftment sites represents a potential therapeutic approach to supplement declining hepatic function in the treatment of liver disease.