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Computational and experimental modeling of cell function in response to 3D oxygen transport in vitro.

细胞功能响应体外 3D 氧运输的计算和实验模型。

基本信息

批准号：
9895842
负责人：
Ian S Kinstlinger
金额：
$ 2.9万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-16 至 2020-11-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895842
关键词：
3-Dimensional Animal Model Architecture Area Behavior Biochemical Biocompatible Materials Biological Assay Biology Blood Blood Vessels Cardiac Output Cell Culture Techniques Cell Death Cell Density Cell Proliferation Cell Survival Cell model Cell physiology Cells Cellular Morphology Characteristics Computer Models Consumption Convection Coupled Cues Diffusion Engineering Environment Equation Evaluation Experimental Models Exposure to Gel Gene Expression Gene Expression Profile Goals HepG2 Hepatic Hepatocyte Heterogeneity Hydrogels Hypoxia Image Impairment In Vitro Incubated Jordan Knowledge Length Link Liver Maps Measurement Measures Metabolic Metabolism Modeling Organ Oxygen Pattern Perfusion Phenotype Physiological Play Population Positioning Attribute Protocols documentation Radial Regenerative Medicine Reproducibility Research Resources Role Structure Supporting Cell Techniques Therapeutic Time Tissue Engineering Tissue Model Tissues To specify Training Validation Variant Vision base biofabrication cell behavior cell type density design design and construction experimental study human tissue imaging Segmentation in vivo insight novel oxygen transport predictive modeling response spatiotemporal three dimensional cell culture three-dimensional modeling transcriptome sequencing

项目摘要

Abstract To advance regenerative medicine towards recapitulating the structures and functions of human tissues at physi- ologic length scales and with relevant cell densities, strategies must be developed to meet their unrelenting metabolic demands. In order to effectively and efﬁciently oxygenate functional engineered tissues, we must understand how changes in oxygen tension modulate cell viability, proliferation, and phenotype. Decades of studying cell cultures incubated under low oxygen levels have unveiled some aspects of the hypoxic response and many key in- sights into its mechanism. Separately, an astonishing array of biomaterials have been developed which can support cells in 3D environments and can recapitulate native cell morphologies and functions to a much greater extent than 2D culture. However, as emerging areas such as regenerative medicine have sought to incorporate cells within these materials, new questions have emerged regarding the roles played by oxygen transport and hypoxia in directing the density and function of the cell populations. Currently, we lack a comprehensive framework to describe and pre- dict how cell populations will alter their densities and functions over time in the presence of spatiotemporally heterogeneous oxygen gradients. We need to extend our knowledge of cellular responses to hypoxia into 3D and we need to proﬁle how tissue-speciﬁc cell functions are impacted by local oxygen cues. In this proposal, I and a sup- porting team of experts in biomaterials, computational modeling, and liver biology will unify computational models of hypoxic response with engineered model tissues to link oxygen transport with tissue function in 3D. Our ﬁndings will be incorporated into an experimentally validated model capable of predicting how cell popula- tions change in density and function in response to speciﬁed oxygen gradients. Cellular responses to hypoxia will be parameterized by cell-speciﬁc response functions and integrated with oxygen transport equations in an agent-based computational model. We will ﬁt parameters using advanced volumetric imaging and image segmentation along with biochemical assays to map cellular markers of viability, proliferation, hypoxia, and phenotype within 3D hydrogels containing HepG2 liver cells, a well-deﬁned model cell type from a highly metabolic tissue. I hypothesize that our closed-loop computational and experimental workﬂow will yield a scalable model of cell behavior at the tissue level which captures previously unstudied functional responses to hypoxia. Finally, to broadly proﬁle the phe- notypic landscape of cells growing in the presence of oxygen gradients, we will use RNA sequencing to map spatial zonation of cell phenotypes along axial and radial oxygen gradients in perfused hydrogels. Controlled encapsulation of cells within hydrogels of reproducible architecture will enable us to evaluate these spatial patterns in gene expres- sion with a degree of experimental control and reproducibility beyond the capabilities of in vivo approaches. Taken together, these studies will provide fundamental insights into how cells respond to local oxygen gradients in 3D environments. Analysis of the spatial heterogeneity introduced by oxygen gradients is also expected to inspire new paradigms for engineering zones of cell function within tissues.

摘要