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Cardiac Regeneration through Growth Factor Eluting Microrod Scaffolds

通过生长因子洗脱微棒支架实现心脏再生

基本信息

批准号：
8496854
负责人：
PAUL H GOLDSPINK
金额：
$ 33.77万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8496854
关键词：
Accounting Address Adverse effects Affect Amino Acids Animal Model Animals Apoptosis Biological Biomedical Engineering Bone Marrow Cardiac Cardiac Myocytes Cell Differentiation process Cell Lineage Cell Maturation Cell Proliferation Regulation Cell Survival Cell physiology Cells Cellular biology Characteristics Chemicals Cicatrix Clinical Collaborations Cues Development Engraftment Evaluation Family Gene Expression Goals Growth Growth Factor Healed Health Care Costs Heart Heart failure Hospitalization Human Hypertrophy Hypoxia In Vitro Infarction Injectable Injection of therapeutic agent Injury Insulin-Like Growth Factor I Kinetics Legal patent Measures Mechanics Mesenchymal Mesenchymal Stem Cells Modeling Molecular Mus Muscle Muscle Cells Myocardial Infarction Myocardial Ischemia Myocardium Natural regeneration Neonatal Outcome Pathologic Pathway interactions Patients Peptides Physiological Physiology Prevention Primary idiopathic dilated cardiomyopathy Pump Rattus Recovery Recovery of Function Recruitment Activity Research Shipping Ships Somatomedins Staging Stem cells Stress System Techniques Technology Tertiary Protein Structure Testing Time Tissue Engineering Tissues United States Variant Ventricular Ventricular Function Work abstracting base cardiac repair cellular engineering design disability burden functional gain healing hypertensive heart disease improved in vivo member migration mortality muscle regeneration novel novel strategies novel therapeutics physical property prevent progenitor prohormone public health relevance repaired scaffold stem stem cell differentiation stem cell population three-dimensional modeling tissue regeneration

项目摘要

DESCRIPTION (provided by applicant): Five million heart failure patients in the US have poor cardiac pumping due to irreversible damage of the contractile myocytes. Thus, recovery of cardiac function by cell and tissue engineering is highly desirable. The novel approach proposed in this application combines bioengineering and cell biology-based techniques to directly target the regeneration of heart muscle, which is an important clinical problem not well addressed by current therapies. We have systemically delivered an artificial stabilized form of the mechano-growth factor (MGF), (24 amino acid, E-domain peptide from the prohormone) that is a member of the insulin-like growth factor (IGF) family and shown recovery of function in failing mouse hearts along with the mobilization of resident progenitor cells. We take advantage of the natural repair capacity of the heart by providing a microrod scaffold (MRS) to not only deliver the native, rapidly degradable MGF, but also provide local mechanical and topographic cues necessary for proper cellular connectivity and differentiation. Our overall hypothesis is that timed release of MGF and IGF-1 delivered locally by the MRS regenerates and strengthens the damaged myocardium without harmful side effects. This is tested on progenitor/stem cells and cardiac myocytes in culture and in animal models. Specific Aim 1 determines the effect of stiffness variation on cells grown in 3D microrod scaffolds. We optimize MRS characteristics for regulation of cell proliferation, lineage commitment, differentiation, contractile maturity and connectivity of stem cells and cardiac myocytes. Specific Aim 2 determines the effect of growth factor (GF)-loaded MRS in environmental conditions that mimic the normal and ischemic heart. We characterize encapsulation efficiency, GF biostability, and acellular release kinetics of the eluting MRS in vitro. We determine effects of GF release from MRS on proliferation and migration of progenitor/ stem and neonatal rat ventricular myocytes to establish changes in gene expression and cell survival under culture conditions that mimic the normal and ischemic heart. Specific Aim 3 determines the cellular, molecular and functional gains that occur at different stages following myocardial infarction after MRS delivery of GFs to the border zone of an infarct. We examine how GF release affects the migration and differentiation of cardiac progenitor cells in vivo. We examine the beneficial effects of localized MGF peptide delivery on cardiac function, prevention of cardiac myocyte apoptosis, prevention of adverse cardiac remodeling, and reduced scar formation. Our long-term goal is to develop microrod MGF therapy that supports the regeneration of cardiac muscle to regain cardiac function in the failing human heart.

描述（由申请人提供）：美国有 500 万心力衰竭患者由于收缩肌细胞的不可逆损伤而导致心脏泵血不良。因此，通过细胞和组织工程恢复心脏功能是非常需要的。该申请中提出的新方法结合了生物工程和基于细胞生物学的技术，直接靶向心肌的再生，这是当前疗法未能很好解决的一个重要的临床问题。我们系统性地输送了人工稳定形式的机械生长因子 (MGF)（24 个氨基酸，来自激素原的 E 结构域肽），它是胰岛素样生长因子 (IGF) 家族的成员，并显示出衰竭小鼠心脏功能的恢复以及驻留祖细胞的动员。我们通过提供微棒支架 (MRS) 来利用心脏的自然修复能力，不仅提供天然的、可快速降解的 MGF，而且还提供适当的细胞连接和分化所需的局部机械和地形提示。我们的总体假设是，MRS 局部定时释放 MGF 和 IGF-1 可以再生并强化受损的心肌，而不会产生有害的副作用。这是在培养物和动物模型中对祖细胞/干细胞和心肌细胞进行测试。具体目标 1 确定刚度变化对 3D 微棒支架中生长的细胞的影响。我们优化 MRS 特性，以调节干细胞和心肌细胞的细胞增殖、谱系定型、分化、收缩成熟度以及连接性。具体目标 2 确定负载生长因子 (GF) 的 MRS 在模拟正常和缺血心脏的环境条件下的效果。我们表征了体外洗脱 MRS 的封装效率、GF 生物稳定性和非细胞释放动力学。我们确定了 MRS 释放的 GF 对祖细胞/干细胞和新生大鼠心室肌细胞增殖和迁移的影响，以确定在模拟正常和缺血心脏的培养条件下基因表达和细胞存活的变化。具体目标 3 确定 MRS 将 GF 递送至梗塞边界区后心肌梗塞后不同阶段发生的细胞、分子和功能增益。我们研究了 GF 释放如何影响体内心脏祖细胞的迁移和分化。我们研究了局部 MGF 肽递送对心脏功能、预防心肌细胞凋亡、预防不良心脏重塑和减少疤痕形成的有益影响。我们的长期目标是开发微棒 MGF 疗法，支持心肌再生，以恢复衰竭人类心脏的心脏功能。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Could interferon-gamma be a therapeutic target for treating heart failure?

DOI：
10.1007/s10741-013-9393-8
发表时间：
2014-03
期刊：
HEART FAILURE REVIEWS
影响因子：
4.6
作者：
Levick, Scott P.;Goldspink, Paul H.
通讯作者：
Goldspink, Paul H.

Localized delivery of mechano-growth factor E-domain peptide via polymeric microstructures improves cardiac function following myocardial infarction.

DOI：
10.1016/j.biomaterials.2014.12.050
发表时间：
2015-04
期刊：
BIOMATERIALS
影响因子：
14
作者：
Pena, James R.;Pinney, James R.;Ayala, Perla;Desai, Tejal A.;Goldspink, Paul H.
通讯作者：
Goldspink, Paul H.

The E-domain region of mechano-growth factor inhibits cellular apoptosis and preserves cardiac function during myocardial infarction.