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Integration of systems and synthetic biology to advance development of human tissues ex vivo

系统与合成生物学的整合促进人体组织离体发育

基本信息

批准号：
10458678
负责人：
Mo Reza Ebrahimkhani
金额：
$ 43.62万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10458678
关键词：
Address Adult Advanced Development Animal Experiments Animals Biliary Biology Biomedical Engineering Biotechnology Cells Clustered Regularly Interspaced Short Palindromic Repeats Computational Biology Computer Analysis Data Dependence Development Disease Endothelium Engineering Epigenetic Process Event FGF2 gene Face Fetal Liver GATA6 transcription factor Gene Activation Genetic Genetic Engineering Genetic Transcription Germ Layers Goals Human Human Development Human Engineering In Vitro Liver Methods Mus Names Organ Organizational Culture Organogenesis Organoids Patients Phenotype Population Reverse engineering Source Stromal Cells Synthetic Genes System Systems Biology Systems Integration Technology Therapeutic Tissue Engineering Tissues Training Transcriptional Activation Transforming Growth Factor beta Vascular Endothelial Cell analog base cell fate specification cell type computational platform drug development fetal gene regulatory network genetic signature genome-wide human adult stem cell human disease human model human stem cells human tissue improved in vivo induced pluripotent stem cell insight inter-individual variation intercellular communication liver injury mouse model novel overexpression precision medicine programs self organization spatiotemporal stem cell derived tissues stem cells synthetic biology tool transcription factor transcriptional reprogramming

项目摘要

The rapidly evolving field of stem cell bioengineering and organoids technology face key challenges: a) stem cell derived tissues are stalled developmentally and show fetal-stage phenotypes b) they often lack key subsets of vascular endothelial and stromal cells derived from different germ layers c) There is a lack of toolset to quantitatively assess cell or tissue identity and d) to guide morphogenetic events towards their native adult phenotypes. In this proposal, we will address these issues by undertaking an integrative synthetic biology and systems biology approach. We recently generated novel human fetal liver organoids ex vivo using human iPSCs. Our approach entails genetic engineering of human iPSCs via overexpression of GATA6 transcription factor in pluripotent media with bFGF and TGF-β. Through this strategy, we showed development of human endodermal and mesodermal, intercellular communications, co-differentiation and self-organization of cultures into a multi- cell type fetal liver organoid. We will employ this tissue as a unique testbed to develop and address biotechnology challenges for in vitro maturation, assessment and engineering of organoids. Through aim 1 of this proposal we will develop and validate a set of genetic toolset to drive cell-fate reprogramming of the multicellular tissue. Through aim 2, we will establish a computational platform to quantitatively assess liver organoids and to identify transcriptional regulators of stage specific development IMPACT: We tackle improvement and assessment of human organoids ex vivo, two key challenges in stem cell bioengineering. The successful completion of this study will result in a hypothesis-driven framework for rational engineering and advancement of stem cell-derived tissues ex vivo. Our study will also generate synthetic liver tissues with close proximity to adult human liver. It reduces dependence on animal experiments and increases access to refined human tissues.

快速发展的干细胞生物工程和类器官技术领域面临着主要挑战：a)干细胞