Induced pluripotent stem cell-derived endothelial cell therapy for liver disease

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Boston Medical Center Corporation $3.517 million on September 4, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to evaluate induced pluripotent stem cell-derived endothelial cell therapy for liver disease.

The research will assess the therapeutic potential of iPSC-derived endothelial cells to promote liver regeneration and alleviate liver disease. The approach leverages the supportive role of liver endothelial cells in enhancing hepatocyte proliferation and function through paracrine signaling. The investigator proposes that engraftment of healthy endothelial cells will restore functional liver vasculature and reconstruct the supportive cellular niche required for hepatocyte proliferation and function, ultimately addressing the scarcity of donor organs for liver transplantation in end-stage and acute liver disease.

Performance occurs in Roxbury, Massachusetts, with a period of performance through August 31, 2030. Boston Medical Center Corporation, a tax-exempt academic medical center and safety-net hospital, serves as the prime recipient. The work builds on the institution's established expertise in supportive interactions between hepatocytes and endothelial cells during liver development, including prior findings on the VEGFA/VEGFR2 axis activation of endothelial cells in injured livers and expression of factors stimulating hepatocyte function.

Abstract

Liver transplantation is the only curative treatment for end-stage and acute liver disease; however, the scarcity of donor organs underscores the urgent need for alternative therapies. Human induced pluripotent stem cells (hipsc) could provide an unlimited supply of patient-specific liver cells for cell-replacement therapy. Although hepatocytes, the primary functional cells of the liver, are the most desirable cell type to transplant, a major limitation is the incomplete maturation of hipsc-derived hepatocytes, which reduces their therapeutic effectiveness, particularly in acute liver diseases that require rapid restoration of functional cells. To overcome this limitation, this application proposes transplanting supportive cells that enhance the proliferation and function of the remaining hepatocytes. We will leverage the well-established supportive role of liver endothelial cells (EC), which promote hepatocyte proliferation and function through paracrine signaling during liver repair. The goal of this proposal is to evaluate the therapeutic potential of ipsc-derived EC (IEC) therapy for promoting liver regeneration. Engraftment of healthy ECS is expected not only to restore functional liver vasculature but also to reconstruct the supportive cellular niche required for the proliferation and function of the remaining hepatocytes, ultimately alleviating liver disease. This approach builds on our long-standing expertise in the supportive interactions between hepatocytes and ECS during liver development. We previously observed that ECS function as a niche that represses WNT and notch signaling to promote hepatocyte generation from pscs, and that this support depends on activation of VEGFR2. Consistent with our findings, others have shown that the vegfa/VEGFR2 axis activates ECS in injured mouse livers, inducing the expression of factors such as WNT2 and HGF that stimulate hepatocyte proliferation. Similarly, WNT2 and WNT9B secreted by ECS have been shown to drive hepatocyte proliferation following partial hepatectomy. To support our proposal, we produced key preliminary data demonstrating the robust generation of iecs that consistently engraft in a murine acute liver injury model induced by monocrotaline (MCT), and that engraftment was significantly enhanced when mice were treated with vegfa mrna formulated in lipid nanoparticles (mrna-LNP). This proposal will thus test the hypothesis that IEC therapy will not only restore damaged liver vasculature but also alleviate the liver dysfunction by promoting the proliferation and function of remaining mature hepatocytes through endothelial-derived factors. Aim 1 will develop strategies to further promote vegfa-mediated IEC engraftment to regenerate a functional hybrid host vasculature in the acute MCT model. Aim 2 will determine the pre-clinical therapeutic benefit of vegfa mrna-LNP-enhanced IEC engraftment in mitigating acute and chronic liver disease features. Aim 3 will define the cellular and molecular mechanisms underlying vegfa-driven IEC therapy. Altogether, this proposal will provide critical insights into the preclinical therapeutic potential of vegfa mrna-LNP-mediated IEC therapy and elucidate the associated cellular and molecular mechanisms for treating acute and chronic liver diseases.