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Extracellular matrix regulation of differentiation via modulation of ILK: application to 3D bioprinting of cardiac tissue

通过调节 ILK 进行细胞外基质分化调节：在心脏组织 3D 生物打印中的应用

基本信息

批准号：
10001078
负责人：
Michael McAlpine
金额：
$ 45.21万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10001078
关键词：
3-Dimensional 3D Print Accounting Activities of Daily Living Acute Address Adult Arteries Behavior Biochemistry Biological Biological Models Bioreactors Blood Vessels Cardiac Cardiac Myocytes Cardiac development Cardiovascular Diseases Cardiovascular Physiology Cause of Death Cell Differentiation process Cells Cessation of life Chemicals Chronic Collagen Type I Core Facility Couples Cyclin-Dependent Kinase Inhibitor 3 Dependence Deposition Developed Countries Dimensions Disease model Drug Screening Elements Endothelial Cells Endothelium Engineering Event Extracellular Matrix Extracellular Matrix Proteins Fibronectins Focal Adhesion Kinase 1 Focal Adhesions Formulation Gene Expression Generations Genes Genetic Transcription Goals Heart Heart Transplantation Human In Vitro Individual Injury Integrins Laboratories Ligation Link Literature Mass Spectrum Analysis Mediating Mesoderm Molecular Motivation Mus Myocardial Myocardial tissue Myocarditis Myocardium Natural regeneration Nutrient Outcome Oxygen Pathway interactions Perfusion Pluripotent Stem Cells Printing Proteins RNA Interference Regulation Research Signal Pathway Signal Transduction Spatial Design Technology Testing Therapeutic Thick Time Tissue Engineering Tissues Toxicity Tests Transcriptional Activation United States arteriole base beta catenin bioprinting cell behavior cell type design glycogen synthase kinase 3 beta inhibitor in vivo induced pluripotent stem cell innovation insight integrin-linked kinase kinase inhibitor matrigel mechanical force meetings muscle form optical imaging organ regeneration programs stem cell differentiation stem cells tissue repair tool transcription factor trend

项目摘要

PROJECT SUMMARY The primary objective of this proposal is to couple a) mechanistic insight relating differentiation outcomes to ECM engagement via intracellular signaling events triggered at the focal adhesion (FA), with b) 3D printing of ECM and ECM-associated proteins as a means to direct cell distribution with maturation and thereby enable fabrication of thick, functional cardiac tissue. The proposal is significant as it has the potential to generate replacement tissues and even heart grafts for individuals suffering from acute and chronic injury to the heart. It is the first of its kind to address the conundrum of the apparent uniformity of the focal adhesion relative to the myriad of different ECM/integrin combinations and the corresponding variety of cell behaviors that emerge from ECM engagement. It does so by proposing that elements of the FA, namely integrin linked kinase (ILK) and associated phosphatase, act as sensitive rheostats that can be co-opted to yield desired behavior. Here, the desired behavior is cardiac differentiation, and the innovation is the utilization of optimized ECM formulations as bioinks to create 3D cardiac tissue mimics (3DCTM) capable of directing cell distribution of multiple cell types with differentiation. This concept is feasible as the Ogle laboratory has long-studied the biochemistry of the ECM and stem cell behaviors associated with ECM engagement, and the McAlpine laboratory has focused on 3D printing of functional materials for a range of applications, from biological to electronic and the merger of these materials. These groups will also interface with expertise of the Kamp lab with respect to their recent generation of induced cardiac progenitor cells (iCPCs) to populate the 3DCTM, the Provenzano lab to assist with molecular mechanisms associated with FA formation, the Garry lab to assist with bioreactor implementation, the Zhang lab to add cardiovascular physiology expertise, and the Talkachova lab to assist with optical imaging to assess function of the 3DCTM and core facilities for mass spectrometry of ECM components and gene editing tools for modulating ILK activity. Together, this expertise will be funneled toward meeting the primary objective of the proposal via the following aims: 1) determine whether activation of integrin-linked kinase (ILK) of focal adhesions or costameres couples integrin activation to β-catenin activation via GSK3β to enable expression of genes associated with cardiomyocyte specification, 2) use 3D ECM-based model systems to identify ECM formulations supportive of endothelial differentiation and assess ILK dependence, and 3) use ECM-based 3D printing to modulate differentiation of cardiac cell types spatially in a cardiac tissue mimic. The motivation for this concept was based on extensive literature search, and results from our own experimentation; the approach was designed to insure that the interpretations of the results are subject to minimal bias and the hypotheses posed are truly tested.

项目总结

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Implementing Biological Pacemakers: Design Criteria for Successful.

DOI：
10.1161/circep.121.009957
发表时间：
2021-10
期刊：
Circulation. Arrhythmia and electrophysiology
影响因子：
0
作者：
Komosa ER;Wolfson DW;Bressan M;Cho HC;Ogle BM
通讯作者：
Ogle BM

Laminin 411 mediates endothelial specification via multiple signaling axes that converge on β-catenin.

DOI：
10.1016/j.stemcr.2022.01.005
发表时间：
2022-03-08
期刊：
STEM CELL REPORTS
影响因子：
5.9
作者：
Hall, Mikayla L.;Givens, Sophie;Santosh, Natasha;Iacovino, Michelina;Kyba, Michael;Ogle, Brenda M.
通讯作者：
Ogle, Brenda M.

Kinases of the Focal Adhesion Complex Contribute to Cardiomyocyte Specification.

局灶性粘附复合物的激酶有助于心肌细胞规范。