Advancing Liver Regeneration: VEGFA mRNA-LNP’s Transformative Role in Hepatocyte Conversion

Significance 

Liver disease treatment is witnessing a revolutionary shift with the advent of innovative therapies targeting cellular regeneration. Vascular Endothelial Growth Factor A (VEGF-A) plays a significant role in liver regeneration, a vital process for maintaining liver function after injury or surgery. VEGF-A is a key protein that primarily promotes angiogenesis, the formation of new blood vessels from pre-existing ones. Growth of new blood vessels ensures an adequate supply of oxygen and nutrients to the regenerating liver tissue. This is essential because the liver has a high metabolic demand, especially during the regeneration process. VEGF-A indirectly supports the proliferation of hepatocytes, the primary functional cells of the liver. By improving blood flow and providing necessary growth factors through enhanced vascular networks, it creates a conducive environment for hepatocyte growth. Liver regeneration involves a controlled inflammatory response. VEGF-A plays a role in modulating this response, which is essential for removing damaged cells and facilitating tissue repair. It also interacts synergistically with other growth factors and cytokines involved in liver regeneration, like Hepatocyte Growth Factor (HGF) and Transforming Growth Factor-beta (TGF-β). These interactions are complex and critical for coordinating the regeneration process. Moreover, VEGF-A directly stimulates the proliferation and survival of endothelial cells, which line the interior surface of blood vessels. This is a key aspect of angiogenesis and hence, liver regeneration. Understanding the role of VEGF-A in liver regeneration has significant clinical implications. It can lead to the development of therapeutic strategies for enhancing liver regeneration in patients with liver diseases or those who have undergone liver resection. In a new study published in Journal CellStemCell led by Professor Valerie Gouon-Evans from Boston Medical School explored a novel approach using Vascular Endothelial Growth Factor A (VEGFA) delivered through lipid nanoparticles (mRNA-LNP), a method that has shown promise in promoting biliary epithelial cell (BEC) to hepatocyte conversion in liver diseases.

The researchers embarked on a meticulous journey to unravel the potential of VEGFA mRNA-LNP in liver regeneration. Their approach involved a series of well-orchestrated experimental models, primarily focusing on mice and zebrafish. The methodology was robust, encompassing various liver injury models, including both acute and chronic conditions induced through specific diets and chemical agents. The application of VEGFA mRNA-LNP was carefully timed and executed, ensuring optimal delivery and efficacy. The study employed cutting-edge techniques like single-cell RNA sequencing and lineage tracing to precisely map the transformation of BECs into hepatocytes. This comprehensive methodological framework was pivotal in establishing a clear and detailed understanding of the cellular mechanisms at play.

The findings of this study mark a pivotal point in liver disease treatment. The ability of VEGFA mRNA-LNP to induce BEC-to-hepatocyte conversion opens a new frontier in regenerative medicine. This approach not only offers a potential alternative to liver transplantation but also sheds light on the intricate cellular mechanisms underlying liver regeneration. The implications of this discovery are vast, extending beyond liver diseases to potentially inform therapies for a range of other conditions where tissue regeneration is crucial. Reflecting on the journey of this research, we see a remarkable transition from theoretical concepts to empirical evidence. The past has been riddled with challenges in liver regeneration, primarily centered around the limited understanding of cellular dynamics and the absence of effective therapeutic agents. This study, however, has pivoted the field into a new era where molecular biology and nanotechnology converge to offer tangible solutions. The utilization of mRNA-LNP technology, especially in the wake of its success in COVID-19 vaccines, has proven to be a game-changer, offering a safe and efficient platform for delivering regenerative molecules like VEGFA.

In conclusion, the study on VEGFA mRNA-LNP as a facilitator of BEC-to-hepatocyte conversion represents a monumental step in liver disease therapy. It exemplifies the power of innovative molecular techniques in deciphering and manipulating biological pathways for therapeutic purposes. This research not only broadens our understanding of liver regeneration but also opens new avenues for treating a myriad of diseases where tissue repair and regeneration are critical. As we stand at the cusp of this new era in medicine, the promise held by such advancements is not just hopeful but transformative, heralding a future where regenerative therapies redefine healthcare and patient outcomes.

Advancing Liver Regeneration: VEGFA mRNA-LNP's Transformative Role in Hepatocyte Conversion - Medicine Innovates
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About the author

Valerie Gouon-Evans, PharmD, PhD

Associate Professor of Medicine
Associate Director of the Molecular & Translational Medicine (MTM) PhD Program of the Department of Medicine.
Boston University Chobanian & Avedisian School of Medicine

After completing her graduate studies in Paris, Dr. Gouon-Evans joined Dr. Pollard’s Lab as a postdoctoral fellow where she studied mammary gland development and breast cancer. She then began her career as an Instructor of Gene and Cell Medicine at the Icahn School of Medicine at Mount Sinai School of Medicine in New York in the laboratory of Dr. Gordon Keller, where she pioneered protocols to efficiently generate hepatocyte-like cells from pluripotent stem cells. She quickly rose up the ranks and was promoted to Assistant Professor before arriving at Boston University. As a PharmD PhD lab leader for 16 years, Dr. Gouon-Evans has overseen the creation of a research program to advance understanding of liver development and establishing therapeutic strategies to alleviate liver disease using an induced pluripotent stem cell platform and mouse models. Recently, Dr. Gouon-Evans lab also pioneered an innovative technology to deliver regenerative factors to the liver to treat various liver diseases, by using mRNA complexed to lipid nanoparticles, which is a validated platform with the widely used mRNA-based COVID-19 vaccines.

Reference

Rizvi F, Lee YR, Diaz-Aragon R, Bawa PS, So J, Florentino RM, Wu S, Sarjoo A, Truong E, Smith AR, Wang F, Everton E, Ostrowska A, Jung K, Tam Y, Muramatsu H, Pardi N, Weissman D, Soto-Gutierrez A, Shin D, Gouon-Evans V. VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis. Cell Stem Cell. 2023 Dec 7;30(12):1640-1657.e8. doi: 10.1016/j.stem.2023.10.008.

Go To Cell Stem Cell.