LyGenesis, Inc., a biotechnology company focused on regenerative medicine founded by McGowan Institute for Regenerative Medicine faculty member Eric Lagasse, PharmD, PhD, recently announced the publication of four peer-reviewed papers on its organ regeneration technology. Dr. Lagasse is LyGenesis’s Chief Scientific Officer, Associate Professor in the Department of Pathology at the University of Pittsburgh, and Director of the Cancer Stem Cell Center at the McGowan Institute. Dr. Lagasse is a co-author on each of the publications.
“For a decade and supported by multiple NIH grants, my laboratory has been laying the scientific foundation for the advancement of our organ regeneration technology. Having previously published work showing that we can use the lymph node as a bioreactor to produce functioning ectopic organs including the liver, pancreas, thymus and kidney, we are now rapidly advancing those technologies, while simultaneously expanding our understanding of the molecular mechanisms that support organogenesis,” said Dr. Lagasse.
LyGenesis’ lead development asset is liver regeneration, which was the focus of the first two papers. “Development of Ectopic Livers by Hepatocyte Transplantation into Swine Lymph Nodes” by Fontes et al. was published in Liver Transplantation, demonstrating that functional mini livers could be grown using the lymph node as a bioreactor. In this swine model using surgically induced liver injuries, liver cells were isolated from the animals and then transplanted into lymph nodes in the abdominal region of the animal. In 100% of the animals, the transplanted liver cells engrafted into the lymph nodes, proliferated, and formed ectopic mini livers, which had the same structure and function as native liver tissue. The cell transplant procedure was safe, well tolerated, and as expected, the amount of liver mass generated by the ectopic livers was proportional to the degree of the native liver’s damage. Paulo Fontes, MD, LyGenesis’s Chief Medical Officer and former Director of the Liver Transplant Program, Starzl Transplant Institute at the University of Pittsburgh Medical Center, is an affiliated faculty member of the McGowan Institute. He is currently a Professor of Surgery and Director, Surgical Innovation & Research, Department of Surgery, West Virginia University Medicine, Morgantown, WV.
“The development and FDA approval of novel therapies for life-threatening diseases requires a rigorous approach to preclinical studies and our ability to grow ectopic organs to support failing organs in patients is no exception,” said Dr. Fontes. “Showing that our cellular therapy was able to safely and effectively induce organogenesis – the forming of a novel, well-vascularized organ within the body – in multiple models of liver disease in large animals was a crucial step toward beginning our forthcoming clinical trial for patients with end stage liver disease who are currently ineligible for standard liver transplantation.”
The second paper, “Ex Vivo Cell Therapy by Ectopic Hepatocyte Transplantation Treats Porcine Tyrosinemia Model of Acute Liver Failure,” by Nicolas and colleagues was published in Molecular Therapy: Methods & Clinical Developments. In this study, a human liver disease (tyrosinemia Type I) was modeled in swine, and liver cells transplanted into lymph nodes were capable of forming ectopic livers that cured all of the animals of otherwise fatal liver disease. The engraftments were again shown to be safe and also structurally and functionally similar to native liver tissue. Maria Giovanna Francipane, PhD, is a co-author on this publication and is Principal Investigator in Regenerative Medicine at Fondazione RiMED in Palermo, an international partnership between the Italian Government, the Region of Sicily, the Italian National Research Council (CNR), the University of Pittsburgh, and UPMC. Also, Dr. Francipane is an affiliated faculty member of the McGowan Institute.
The other two published peer-reviewed papers focused on kidney regeneration. “Kidney–in–a–Lymph Node: A Novel Organogenesis Assay to Model Human Renal Development and Test Nephron Progenitor Cell Fates” published in The Journal of Tissue Engineering and Regenerative Medicine by Francipane and colleagues replicated and extended previous findings in mice showing that human ectopic kidney tissues could also be grown using the lymph node as a bioreactor. The paper also demonstrated the lymph node’s remarkable ability to promote vascularization, a key rate-limiting issue for many transplant technologies, which brings blood flow and effective oxygenation to ectopic organs including kidney tissues engrafted into lymph nodes. In the paper, “Host Lymphotoxin-ß Receptor Signaling is Crucial for Angiogenesis of Metanephric Tissue Transplanted into Lymphoid Sites,” published in The American Journal of Pathology, Francipane and colleagues have begun to unravel some of the molecular signaling – focusing on the lymphotoxin-ß receptor (LTßR) pathway in particular – that appears to be crucial for engrafted kidney tissue to grow and function properly.
Abstract (Fontes P, Komori, J, Lopez, R, Marsh, W, Lagasse, E. Development of ectopic livers by hepatocyte transplantation into swine lymph nodes. Liver Transplantation, 2020.)
Abstract (Nicolas CT, Kaiser RA, Hickey RD, Allen KL, Du Z, VanLith CJ, Guthman RM, Amiot B, Suksanpaisan L, Han B, Francipane MG, Cheikhi A, Jiang H, Bansal A, Pandey MK, Garg I, Lowe V, Bhagwate A, O’Brien D, Kocher J-PA, DeGrado TR, Nyberg SL, Lagasse E, Lillegard JB. Ex vivo cell therapy by ectopic hepatocyte transplantation treats the porcine tyrosinemia model of acute liver failure. Molecular Therapy: Methods & Clinical Development, 2020.)
Abstract (Francipane MG, Han B, Oxburgh L, Sims–Lucas S, Li Z, Lagasse E. Kidney–in–a–lymph node: A novel organogenesis assay to model human renal development and test nephron progenitor cell fates. Journal of Tissue Engineering and Regenerative Medicine, 2019;13:1724–1731.)
Abstract (Maria Giovanna Francipane, Bing Han, Eric Lagasse. Host lymphotoxin-β receptor signaling is crucial for angiogenesis of metanephric tissue transplanted into lymphoid sites. The American Journal of Pathology, 2020 Jan;190(1):252-269.)