Stem Cells and Dynamic Materials Improve Cardiac Function Post-mycardial Infarcti

干细胞和动态材料改善心肌梗塞后的心脏功能

• 批准号: 8296617
• 负责人: Adam J Engler
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296617
• 关键词: A Mouse; Address; Age; Animal Model; Antibodies; Atomic Force Microscopy; B-Lymphocytes; Benchmarking; Biological Assay; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiomyoplasty; Cause of Death; Cell Aging; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cells; Cicatrix; Collagen; Competitive Binding; Congestive Heart Failure; Control Animal; Coronary artery; Cues; Detergents; Differentiation Antigens; EFRAC; Engineering; Engraftment; Ensure; Environment; Ethylmaleimide; Extracellular Matrix; Failure; Fertilization; Foreign-Body Reaction; Gel; Genes; Growth Factor; Heart; Histology; Hour; Hyaluronic Acid; Hyaluronidase; Hydrogels; Immunofluorescence Immunologic; In Vitro; Infarction; Injectable; Injection of therapeutic agent; Injury; Label; Left; Measurement; Measures; Mesenchymal Stem Cells; Metabolic; Methods; Modeling; Monitor; Muscle; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Necrosis; Osteoblasts; Outcome; Physiologic intraventricular pressure; Polymerase Chain Reaction; Property; Rattus; Relative (related person); Sarcomeres; Shapes; Site; Sprague-Dawley Rats; Stem cells; Structure; Sulfhydryl Compounds; Supplementation; Surface; Techniques; Testing; Therapeutic; Time; Tissue Engineering; Tissues; United States; adult stem cell; angiogenesis; base; biomaterial compatibility; bone; cell age; cell behavior; cell type; crosslink; cytotoxicity; design; embryonic stem cell; functional restoration; heart function; improved; in vivo; novel; novel strategies; polyacrylamide gels; prevent; progenitor; regenerative therapy; response; scaffold; subcutaneous

DESCRIPTION (provided by applicant): The fibrotic scar that results after a myocardial infarction (MI) is stiff extracellular matrix (ECM), owing to the enhanced secretion of collagen as the tissue thins and undergoes necrosis. Pervious methods to improve myocardial function post-MI, e.g. cardiac patches and cell injections, do not sufficiently mimic the intrinsic properties of the matrix, such as stiffness (denoted E). Moreover, they often employ adult stem cells which have not been shown to have significant remodeling capacity and instead are more responsive to aberrant matrix conditions; thus cells have been observed to improperly differentiate into osteoblast-like cells or to fail to differentiate altogether in infarcted myocardium that is 3-fold too stiff, i.e. EInfarct >> ECARDIO. We have recently developed a dynamic, thiol-modified hyaluronic acid (HA-S)-based hydrogel that displays developmentally appropriate stiffness over time via time-dependent crosslinking. We have also shown that this can improve cardiac progenitor differentiation in mature cardiomyocytes by nearly an order of magnitude over soft matrix that does not remodel. In this proposal, we will first extend our findings to embryonic stem cells (ESCs), which should be even more effective at matrix remodeling than previous stem cell types. Expression of cardiac-specific genes in 2D and 3D HA-S hydrogels will first be monitored in ESCs to determine if HA-S can induce cardiomyogenesis relative to cardiac progenitor cells and age-matched control animals, and if not, at least ensure that it enhances differentiation over HA-S hydrogels that have had their time-dependent crosslinking removed by treatment with iodacetamide. Matrix secretion, assembly, and remodeling (via degradation by hyaluronidase) will also be measured and compared to cardiac progenitor cells to ensure that ESCs can indeed remodel matrix effectively and that cells can migrate sufficiently in the material. Cells and HA-S hydrogels will subsequently be used in a subcutaneous rat model to ensure biocompatibility and monitor hydrogel properties in vivo, e.g. time-dependent stiffening. Finally in a rat model of MI, ESCs and/or cardiac progenitor will be used in conjunction with the HA-S to determine to what degree our HA-S hydrogel can improve myocardial function post-MI versus convention treatments, e.g. cell injection.

描述(申请人提供)：心肌梗死(MI)后导致的纤维性瘢痕是僵硬的细胞外基质(ECM)，原因是随着组织变薄和坏死，胶原蛋白的分泌增加。以往改善心肌梗死后心肌功能的方法，如心脏补片和细胞注射，不能充分模拟基质的固有属性，如硬度(表示为E)。此外，他们经常使用成年干细胞，这些干细胞尚未被证明具有显著的重塑能力，相反，它们对异常的基质条件更敏感；因此，人们观察到，在过于僵硬3倍的梗塞心肌中，细胞不正确地分化为成骨样细胞，或者完全无法分化，即EInfarct&gt；eCardio。我们最近开发了一种动态的硫醇修饰的透明质酸(HA-S)水凝胶，它通过时间依赖的交联会随着时间的推移表现出发育适当的硬度。我们还表明，这可以改善成熟心肌细胞的心脏前体细胞分化，比不重塑的软基质高出近一个数量级。在这项提案中，我们将首先将我们的发现扩展到胚胎干细胞(ESCs)，它在基质重塑方面应该比以前的干细胞类型更有效。首先将在胚胎干细胞中监测2D和3D HA-S水凝胶中心脏特异基因的表达，以确定HA-S是否能够相对于心脏祖细胞和年龄匹配的对照组动物诱导心肌生成，如果不能，至少确保它促进了与HA-S水凝胶的分化，后者已经通过碘乙酰胺处理消除了其时间依赖的交联。还将测量基质分泌、组装和重塑(通过透明质酸酶降解)，并与心脏前体细胞进行比较，以确保ESCs确实可以有效地重塑基质，并确保细胞能够在材料中充分迁移。细胞和HA-S水凝胶随后将用于大鼠皮下模型，以确保生物相容性和监测体内的水凝胶特性，例如时间依赖的僵硬。最后，在心肌梗死大鼠模型中，胚胎干细胞和/或心脏祖细胞将与HA-S联合使用，以确定与常规治疗(如细胞注射)相比，我们的HA-S水凝胶在多大程度上可以改善心肌梗死后的心肌功能。

项目成果

Hydrogels with time-dependent material properties enhance cardiomyocyte differentiation in vitro.

• DOI: 10.1016/j.biomaterials.2010.10.020
• 发表时间: 2011-02
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Young, Jennifer L.;Engler, Adam J.
• 通讯作者: Engler, Adam J.

In vivo response to dynamic hyaluronic acid hydrogels.

• DOI: 10.1016/j.actbio.2013.03.019
• 发表时间: 2013-07
• 期刊: ACTA BIOMATERIALIA
• 影响因子: 9.7
• 作者: Young, Jennifer L.;Tuler, Jeremy;Braden, Rebecca;Schuep-Magoffin, Pamela;Schaefer, Jacquelyn;Kretchmer, Kyle;Christman, Karen L.;Engler, Adam J.
• 通讯作者: Engler, Adam J.

The alignment and fusion assembly of adipose-derived stem cells on mechanically patterned matrices.

• DOI: 10.1016/j.biomaterials.2012.06.057
• 发表时间: 2012-10
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Choi, Yu Suk;Vincent, Ludovic G.;Lee, Andrew R.;Kretchmer, Kyle C.;Chirasatitsin, Somyot;Dobke, Marek K.;Engler, Adam J.
• 通讯作者: Engler, Adam J.

Mechanosensitive kinases regulate stiffness-induced cardiomyocyte maturation.

• DOI: 10.1038/srep06425
• 发表时间: 2014-09-19
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Young JL;Kretchmer K;Ondeck MG;Zambon AC;Engler AJ
• 通讯作者: Engler AJ

Rotator cuff tear state modulates self-renewal and differentiation capacity of human skeletal muscle progenitor cells.

• DOI: 10.1002/jor.23453
• 发表时间: 2017-08
• 期刊: Journal of orthopaedic research : official publication of the Orthopaedic Research Society
• 作者: Thomas KA;Gibbons MC;Lane JG;Singh A;Ward SR;Engler AJ
• 通讯作者: Engler AJ