The effect of donor age on the function and therapeutic efficacy of human hepatocyte-like cells

供者年龄对人肝细胞样细胞功能及治疗效果的影响

• 批准号: 10646093
• 负责人: Varvara A Kirchner
• 金额: $ 16.51万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646093
• 关键词: Acute Liver Failure; Address; Adult; Affect; Age; Age-Years; Allogenic; Animals; Architecture; Attention; Autologous; Bilirubin; Biological Assay; Biology of Aging; Bypass; Cell Differentiation process; Cell Maturation; Cell Therapy; Cell Transplantation; Cell physiology; Cells; Cessation of life; Clinical; Cytochrome P450; DNA Methylation; DNA Methyltransferase Inhibitor; Data; Development Plans; Diabetes Mellitus; Diagnosis; Differentiated Gene; Disease; Disease model; Elderly; Engraftment; Epigenetic Process; Ethics; Exhibits; Future; Gene Expression; Genes; Genetic; Genus Hippocampus; Goals; Hepatic; Hepatocyte; Hepatocyte transplantation; Human; Human Activities; Immune response; In Vitro; Liver; Liver Failure; Liver diseases; Macular degeneration; Mass Spectrum Analysis; Measures; Mentors; Metabolic; Metabolism; Monitor; Morbidity - disease rate; Mus; Operative Surgical Procedures; Organ; Organ Transplantation; Oxygen Consumption; Pathology; Patients; Persons; Pharmacy (field); Play; Positioning Attribute; Proteins; Proteome; Protocols documentation; Publishing; Regenerative Medicine; Regulation; Research Personnel; Risk Factors; Role; Serum Albumin; Solid; Source; Technology; Testing; Training; Transaminases; Transcript; Transplant Surgeon; Transplantation; Treatment Efficacy; Tyrosinemias; age group; age related; aged; alternative treatment; career; career development; cell age; clinical application; embryonic stem cell; epigenetic regulation; epigenome; experience; hepatocyte engraftment; in vivo; induced pluripotent stem cell; liver transplantation; metabolic profile; minimally invasive; mortality; mouse model; multiple omics; novel; operation; preservation; prevent; stem cell biology; stem cells; success; therapeutic evaluation; transcriptome; transcriptome sequencing

Project Summary: Worldwide, 844 million people are afflicted with liver disease, with mortality nearing 2 million deaths per year. Liver transplantation is the preferred treatment for selected cases but is limited by the availability of high-quality organs from young donors (<55 years old), and the morbidity associated with the operation. Cell-based therapy using primary human hepatocytes (PHHs) is a minimally invasive alternative for treatment of select liver pathologies where architecture is preserved but there are metabolic derangements, such as in acute liver failure and metabolic liver disease. Optimal metabolic function of the cells is critical for the success of cell-based therapies. However, PHH therapy is severely limited by the scarcity of donors, and the dramatic decrease in metabolic function of PHHs from older donors. Human hepatocyte-like cells (h-iHLCs) derived from human induced pluripotent stem cells (h-iPSCs) emerged as an alternative to PHHs for treatment of select liver conditions. H-iHLC have three benefits: (1) H-iHLCs are produced from an unlimited, renewable source: h-iPSCs. (2) They bypass ethical concerns associated with the use of embryonic stem cells. (3) They have the potential to prevent an allogeneic immune response following transplantation by utilizing the patients’ own cells. Although, the deleterious impact of age on the metabolic function has been described for PHHs, the impact of donor age on the metabolism in h-iHLCs has not been studied. Here, we aim to identify the donor age-associated changes in the overall metabolic profile of h-iHLCs by studying the transcriptome and proteome of h-iHLCs from young and old donors and compare the results to PHHs from the same donors. We will study in detail the expression and function of the cytochrome P450 (CYP450) superfamily in h-iHLCs and PHHs as a function of donor age. Age-related changes in DNA-methylation down-regulate metabolic function including CYP450 activity in PHHs. Therefore, we will study and attempt to modulate this regulatory mechanism in h-iHLCs with the goal to optimize the overall metabolic function including CYP450 activity in h-iHLCs. We will examine the therapeutic efficacy of the generated h-iHLCs in a murine model of acute liver failure by transplanting h-iHLCs into metabolic liver failure, tyrosemia type I (Fah¯′¯/Rag2¯′¯/Il2rg¯′¯ on NOD-strain background (FRGN)) mice. The results from this study will provide critical information about the impact of donor age on metabolism and its regulation in h-iHLCs and will (1) assist in selecting metabolically fit donors for allogeneic h-iHLCs transplantation, (2) allow future modulation of functional and regulatory mechanisms through alterations in reprogramming, differentiation and gene editing, to produce high-quality h-iHLCs with optimized metabolic function for allo- and autogeneic transplantation.

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