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A multi-modular approach for human pluripotent stem cell-based liver regeneration

基于人类多能干细胞的肝再生的多模块方法

基本信息

批准号：
10670221
负责人：
VALERIE B GOUON-EVANS
金额：
$ 53.6万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670221
关键词：
Acceleration Acute Address American BMP4 CEBPA gene Cell Communication Cell Line Cell Survival Cell Therapy Cell Transplantation Cell physiology Cells Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Complex Data EGF gene Endothelial Cells Endothelium Engineering Engraftment Epidermal Growth Factor Receptor Exhibits Fibroblasts Generations Genetic Goals Hepatic Hepatocyte Hepatocyte transplantation Human Human Engineering IL6 gene In Vitro Individual Injections KDR gene Ligands Liver Liver Failure Liver Regeneration Liver diseases Mediating Messenger RNA Mitogen Receptors Mitogens Modeling Mus Natural regeneration Nucleosides Partial Hepatectomy Pathway interactions Patients Proliferating Receptor Activation Recombinant Proteins Recombinants Regenerative capacity Regenerative pathway Repression Role Safety Signal Transduction Specific qualifier value Technology Testing Therapeutic Transplantation United States VEGFA gene WNT2 gene Waiting Lists acute liver injury beta catenin cancer clinical trial cancer immunotherapy cell replacement therapy cellular engineering chronic liver injury clinical translation clinically relevant directed differentiation end stage liver disease experimental study human pluripotent stem cell improved in vivo in vivo engraftment induced pluripotent stem cell injured lipid nanoparticle liver cell proliferation liver development liver injury liver repair liver transplantation mouse model notch protein novel overexpression receptor regenerative tool transcription factor

项目摘要

PROJECT SUMMARY Liver transplantation is currently the only treatment for acute and chronic liver failure. Given the shortage of donor livers, hepatocyte transplantation is considered a potential treatment for liver diseases and a bridge for patients awaiting liver transplantation, but its application has been hampered by a limited supply of hepatocytes. Human induced pluripotent stem cell (hiPSC) could provide an unlimited supply of patient-specific hepatocytes for cell replacement therapy. However, generation of hiPSC-derived hepatocyte like cells (HLCs) that repopulate a damaged liver remains a challenge, and a major gap that this application targets. Obstacles to HLC therapy include poor cell engraftment and insufficient maturation. Thus to fill this gap, we propose a multi- modular approach that includes (1) a bi-cell therapy composed of HLCs and supportive endothelial cells (ECs), both derived from hiPSCs (2) engineering HLCs with novel genetic circuit technology to promote their engraftment and maturation and (3) engineering ECs to support HLC-mediated liver repair. This approach is based on our long-standing expertise in the directed differentiation of PSCs to HLCs having pioneered the use of BMP4 to induce hepatic specification, an approach now utilized widely in the field. We initially observed that ECs were always associated with mouse ESC-derived HLC clusters, and showed that ECs function as a niche to repress Wnt and Notch signaling to promote HLC specification. Recently, we discovered that this EC supportive function is dependent on activation of VEGFR2. Consistent with our data, it has been shown that a VEGFA-VEGFR2 axis activates sinusoidal ECs in injured mouse livers to induce the expression of factors such as WNT2 and HGF that trigger hepatocyte proliferation. Similarly, WNT2 and WNT9b secreted by sinusoidal ECs were shown to induce hepatocyte proliferation following partial hepatectomy. Thus, bi-cell therapy with ECs represents a potential strategy to overcome the obstacles of HLC therapies. In addition, we will enhance EC supportive functions through modulation of VEGFR2 and downstream factors such as HGF, WNT2 and WNT9b. In parallel, we will engineer HLCs to activate mitogen receptors cMET, EGFR and IL6R and express transcription factors (ATF5, PROX1, CEBPA) that are critical for liver development, regeneration and the maturation of reprogrammed fibroblast-derived HLCs. We will test that these pathways and TFs accelerate HLC engraftment and maturation following bi-cell therapy. This proposal may have major clinical implications as VEGFR2, cMET, EGFR and IL6R will be activated in vivo using the clinically safe lipid nanoparticle-complexed non- integrative nucleoside-modified mRNA (mRNA-LNP). Our preliminary data indicate that mRNA-LNP encoding HGF, EGF and IL6 significantly improve HLC survival after transplantation into liver injury mouse models. Our central hypothesis is thus: a bi-cell therapy with HLCs and ECs engineered to promote the EC niche-HLC crosstalk in combination with the unprecedented mRNA-LNP tool and genetic circuit hiPSC lines that this application will pioneer in the liver cell therapy field will lead to successful HLC-based treatment for liver disease.

项目总结