Quantitative molecular and cellular MRI of hepatocyte transplantation

肝细胞移植的定量分子和细胞MRI

• 批准号: 9006872
• 负责人: Erik Shapiro
• 金额: $ 48.93万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9006872
• 关键词: Age; Algorithms; Animal Model; Biology; Biopsy; Blood; Cell Count; Cell Line; Cell Transplantation; Cell Transplants; Cells; Clinical; Clinical Trials; Collaborations; Computer Vision Systems; Contrast Media; Coupled; Data; Data Analyses; Dependence; Detection; Development; Disease model; Engraftment; FDA approved; Family suidae; Flow Cytometry; Future; Germ Cells; Hepatocyte; Hepatocyte transplantation; Histology; Human; Image; Image Analysis; Individual; Iron; Label; Liver; Liver Failure; Liver diseases; Machine Learning; Magnetic Resonance Imaging; Malignant neoplasm of liver; Maps; Measurement; Measures; Methodology; Methods; Modeling; Molecular; Monitor; Mus; Organ Donor; Outcome; Patients; Pattern Recognition; Physicians; Protocols documentation; Regenerative Medicine; Regimen; Research; Research Personnel; Resolution; Scheme; Spatial Distribution; Spottings; Staging; Stem cells; System; Testing; Time; Tissues; Translations; Transplantation; Weight; Wit; Work; Xenograft procedure; base; design; effective therapy; embryonic stem cell; hepatocyte engraftment; improved; innovation; interdisciplinary approach; islet; liver transplantation; molecular imaging; mouse model; novel; pre-clinical research; public health relevance; research study; success; tool; uptake

 DESCRIPTION (provided by applicant): For many severe liver diseases, the only effective treatment is liver transplantation. Unfortunately, due to the shortage of available donor organs, or the patient's age, liver transplantation is not available to all patients. Hepatocyte transplantation (HTx) is an alternative, experimental treatment, with limited long term success in humans. A major unsolved question is how can we dynamically monitor and quantify cell transplantation in HTx to help improve HTx and to closely monitor clinical implementation? To answer this question, we combine an innovative molecular and cellular MRI approach, with machine learning and computer vision, to non-invasively quantify cell engraftment and long term engraftment and repopulation (LTER) in the liver following HTx. Using a mouse model that facilitates LTER following HTx, we will use this combined approach to quantify transplanted cells in the liver at Days 1 and 7 after HTx, reflecting the timings of initial cell delivery (Day 1) and actual cellular engraftment in the tissue (Day 7). Then, we will measure LTER of these cells in the liver 30 - 90 days post-transplant, making innovative use of Eovist, an FDA approved MRI contrast agent specific for healthy hepatocytes. These experiments will evaluate mouse donor cells, as well as pig primary hepatocytes and pig embryonic stem cell-derived hepatocyte cell line. This transformative work will be the first study to achieve this level of quantification wit molecular and cellular MRI of regenerative medicine, in any animal model. Additionally, we will test pattern recognition algorithms aimed at predicting the outcome of LTER, at an early stage. The capability to predict LTER outcome would be paradigm shifting as it would enable physicians to consider additional HTx regimens or second line treatments if HTx fails. This is seldom possible. Though this project will be developed on mice, clinical translation of the imaging protocol would be straightforward because the exact imaging and data analysis scheme that we use to measure HTx in mouse, can be used to measure HTx in humans. Eovist is FDA approved for use in humans with liver disease, and MRI-based cell tracking of iron labeled cells is in clinical trials. Our preliminary data strongly suggests that MRI and data analysis can discriminate single cells at 200 µm resolution, meaning the MRI could likely be performed on any high field human MRI system. Additionally, the discovery that a stem cell-derived hepatocyte achieved even partial LTER would be extremely encouraging for exploring human and/or pig stem cell-derived hepatocytes for human use, because these cells can potentially alleviate the crucial issue of poor cell supply, similar to progress seen in pig islet transplant. The proposed research takes a multidisciplinary approach with expertise in hepatocyte transplant and biology, molecular imaging, machine learning/computer vision, and mouse liver disease models. Collaboration among the researchers is ongoing with extensive preliminary data across all aspects of the proposed work.

 描述（申请人提供）：对于许多严重的肝脏疾病，唯一有效的治疗方法是肝移植。不幸的是，由于可用供体器官的短缺或患者的年龄，肝移植并不适用于所有患者。肝细胞移植（HTx）是一种替代性实验性治疗方法，但在人类身上取得的长期成功有限。一个尚未解决的主要问题是我们如何动态监测和量化 HTx 中的细胞移植，以帮助改善 HTx 并密切监测临床实施情况？ 为了回答这个问题，我们将创新的分子和细胞 MRI 方法与机器学习和计算机视觉相结合，以非侵入性方式量化 HTx 后肝脏中的细胞植入和长期植入和再增殖 (LTER)。使用促进 HTx 后 LTER 的小鼠模型，我们将使用这种组合方法来量化 HTx 后第 1 天和第 7 天肝脏中移植的细胞，反映初始细胞递送的时间（第 1 天）和 组织中的实际细胞植入（第 7 天）。然后，我们将在移植后 30 - 90 天测量肝脏中这些细胞的 LTER，创新地使用 Eovist，这是一种 FDA 批准的针对健康肝细胞的 MRI 造影剂。这些实验将评估小鼠供体细胞以及猪原代肝细胞和猪胚胎干细胞衍生的肝细胞系。 这项革命性的工作将是第一个在任何动物模型中利用再生医学的分子和细胞 MRI 实现这种量化水平的研究。此外，我们将测试旨在早期预测 LTER 结果的模式识别算法。预测 LTER 结果的能力将是范式转变，因为如果 HTx 失败，它将使医生能够考虑额外的 HTx 治疗方案或二线治疗。这很少可能。 尽管该项目将在小鼠身上开发，但成像方案的临床转化将很简单，因为我们用于测量小鼠 HTx 的精确成像和数据分析方案也可用于测量人类 HTx。 Eovist 已获 FDA 批准用于患有肝病的人类，基于 MRI 的铁标记细胞追踪正在进行临床试验。我们的初步数据强烈表明 MRI 和数据分析可以以 200 µm 分辨率区分单个细胞，这意味着 MRI 可以在任何高场人体 MRI 系统上进行。此外，干细胞衍生的肝细胞甚至实现了部分 LTER 的发现对于探索人类和/或猪干细胞衍生的肝细胞供人类使用将​​是非常令人鼓舞的，因为这些细胞可以潜在地缓解细胞供应不良的关键问题，类似于猪胰岛移植中所取得的进展。 拟议的研究采用多学科方法，具有肝细胞移植和生物学、分子成像、机器学习/计算机视觉和小鼠肝病模型方面的专业知识。研究人员之间的合作正在进行，涉及拟议工作的各个方面的广泛初步数据。