Generating human surrogate hepatocytes by integration- and oncogene-free lineage reprogramming
Final Report Abstract
Chronic injuries to the liver result in repeated hepatocyte death and a scarring response known as fibrosis which is mainly driven by hepatic myofibroblasts (MF) that deposit collagen in the liver. In persisting liver injury, liver fibrosis progresses to cirrhosis as the end-stage of chronic liver diseases. Currently, liver transplantation is the only effective treatment for cirrhosis, but donor liver scarcity and complications from immune-suppressive medications have prompted research for therapeutic alternatives. Liver cell transplantation of either primary hepatocytes or reprogrammed hepatocytes (iHeps) from autologous cell sources are attractive approaches but in cirrhotic livers, a major hurdle is long-term engraftment. As a solution to these problems, we developed in vivo hepatic reprogramming of MFs into hepatocytes to overcome the need for engraftment and limit the collagen deposition. We identified a naturally occurring adeno-associated virus (AAV) capsid, AAV6, as effective in transducing MFs and established the direct reprogramming of MFs into iHeps (MF-iHeps) in vivo using AAV6. MF-iHeps function and proliferate in vivo similarly to primary hepatocytes and reduce liver fibrosis. We also established hepatic reprogramming of human MFs using AAV6. Since AAVs are already used in clinical trials, this approach has potential for clinical translation. Radio interviews with Milad Rezvani on liver disease research, Science Today on CBS radio news, broadcasted July 5, 13 and 28.
Publications
- Generating Hepatocytes (2016), United States Patent Number 20150175962
Zhu S, Ding S, Willenbring H, Rezvani M, Harbell J
- “In vivo reprogramming of myofibroblasts into hepatocytes as a therapy for liver fibrosis”, Presidential Plenary Presentation at the 66th Annual The Liver Meeting 2015 of the American Association for the Study of Liver Diseases (AASLD), San Francisco, CA, October 23rd 2015
Rezvani M
- Assessing the Therapeutic Potential of Lab-Made Hepatocytes. Hepatology. 2016 Jul;64(1):287-94
Rezvani M, Grimm A, Willenbring H
(See online at https://doi.org/10.1002/hep.28569) - Epigenetics Hitting Heart - On “Bmi1 is a Key Epigenetic Barrier to Direct Cardiac Reprogramming”, First Author Journal Club: 2016 Selections. Cell Stem Cell. 2016 Jun 2;18(6):692-94
Rezvani M, Español-Suñer R, Malato Y, Dumont L
- In vivo hepatic reprogramming of myofibroblasts as a therapeutic strategy for liver fibrosis. Cell Stem Cell. 2016 Jun 2;18(6):809-16
Rezvani M, Español-Suñer R, Malato Y, Dumont L, Grimm AA, Kienle E, Bindmann J, Wiedtke E, Bernadette Y. Hsu, Naqvi SJ, Schwabe RF, Carlos U. Corvera, Grimm D, Willenbring H
(See online at https://doi.org/10.1016/j.stem.2016.05.005) - Physiological Ranges of Matrix Rigidity Modulate Primary Mouse Hepatocyte Function In Part Through Hepatocyte Nuclear Factor 4 Alpha. Hepatology. 2016 Jul;64(1):261-75
Desai S, Tung J, Zhou V, Grenert J, Malato Y, Rezvani M, Espanol-Suner R, Willenbring H, Weaver V, Chang T
(See online at https://doi.org/10.1002/hep.28450)
