Autologous Cardiomyocytes from Masseter Muscles to Repair Myocardial Infarction (MI)

咬肌自体心肌细胞修复心肌梗死 (MI)

• 批准号: 9332765
• 负责人: W Sean Davidson
• 金额: $ 44.98万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-06 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332765
• 关键词: Adult; Alpha Cell; Animal Model; Animals; Autologous; Biological Process; Blood flow; Cardiac; Cardiac Myocytes; Cardiovascular system; Cause of Death; Cell Differentiation process; Cell Transplantation; Cells; Chromatin; Clinical; Data; Development; Developmental Biology; EFRAC; Engraftment; Epigenetic Process; Family suidae; Fibrosis; Gene Expression; Gene Expression Profile; Genetic; Harvest; Heart; Heart Atrium; Heart failure; Human; Hypertrophy; In Vitro; Knockout Mice; Laboratories; Left; Limb structure; Mandible; Masseter Muscle; Mediating; MicroRNAs; Miniature Swine; Modeling; Motor; Mus; Muscle; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocardium; Outcome; Overlapping Genes; Pacemakers; Patients; Phenotype; Population; Process; Regenerative Medicine; Regulation; Risk; Safety; Secondary to; Series; Skeletal Muscle; Somatic Cell; Sorting - Cell Movement; Source; Stem cells; Surface; Techniques; Testing; Time; Tissues; Transplantation; Treatment Efficacy; Ventricular; base; cardiogenesis; coronary artery occlusion; design; effective therapy; experimental study; heart cell; heart function; implantation; improved; in vivo; innovation; insight; interstitial; motor disorder; myocardial damage; myogenesis; nerve supply; novel; personalized medicine; progenitor; regenerative therapy; repaired; restoration; satellite cell; skeletal; targeted treatment; therapeutic candidate; transcription factor; transdifferentiation; tumor

Abstract Myocardial infarction (MI) is caused by lack of adequate blood flow to the heart and results in terminal loss of cardiomyocytes (CM). MI and its related complications are a leading cause of death worldwide. The search for regenerative therapy that can repair or replace lost CM remains a daunting challenge. The foremost issue is the difficulty in procuring viable replacement cells. Heterologous sources are unattractive due to the potential for immunorejection. Harvesting progenitor cells from a patient's damaged heart is invasive and poses severe risks. Reprogramming somatic cells from other autologous sources can result in very low yields due to genetic or epigenetic barriers. A series of recent studies, however, has revealed that masseter muscle derived progenitor (MMP) cells share a common origin and have overlapping gene expression patterns with heart muscle. MMP can be isolated from highly accessible masseter muscles without mandible motor dysfunction and our preliminary data has shown that MMP yield the highest rate of CM differentiation as compared with limb muscle progenitors. Importantly, MMP can give rise to functional CM phenotypes including ventricular, atrial, and pacemaker CM under defined conditions. Therefore, MMP represent an ideal therapeutic candidate to maximize cardiogenic differentiation efficiency after cell transplantation in order to repopulate an infarcted heart region with a supply of autologous CM. At the same time, MMP avoid the common pitfalls associated with immunorejection, tumor formation, and reversion to an alternative epigenetic precursor. Aim 1 consists of in vitro studies to isolate and characterize MMP (including developmental origin, surface markers, and proliferation potential) in order to gain the desired CM population using novel sorting approaches. Aim 2 is designed to determine the mechanism by which microRNAs and transcription factor networks mediate the lineage commitments of MMP and the underlying cardiac potential of MMP as regulated by miR-128. Finally, Aim 3 focuses on the effects of implantation of MMP-derived cell sheets on the cardiac functions in mouse and porcine MI models. Experiments will examine the in vivo cell fate of MMP and determine any beneficial effects that result from cell engraftment and functional integration under ischemic conditions. These studies will provide new insights in both basic heart developmental biology and cell-based regenerative medicine. This approach holds great promise for the emerging field of personalized medicine and strongly supports the possibility that autologous MMP harvested from human masseter muscles and expanded in vitro will serve as a major source of CM that will be highly effective for treatment of patients after MI.

摘要 心肌梗死（MI）是由于缺乏足够的血液流向心脏，导致终末损失 心肌细胞（CM）。心肌梗死及其相关并发症是全球死亡的主要原因。的 寻找能够修复或替换丢失CM的再生疗法仍然是一个令人生畏的挑战。的 最重要的问题是难以获得有活力的替代细胞。异质性来源是没有吸引力的 因为有可能发生免疫排斥反应从病人受损的心脏中获取祖细胞 具有侵入性并具有严重风险。来自其他自体来源的体细胞重编程可导致 由于遗传或表观遗传障碍，产量非常低。然而，最近的一系列研究表明， 咬肌源性祖细胞（MMP）具有共同的起源，并具有重叠的基因 心肌的表达模式。MMP可以从高度可及的咬肌中分离出来 没有下颌运动功能障碍，我们的初步数据表明，MMP产生的最高率， CM分化与肢肌祖细胞相比。重要的是，MMP可以产生功能性的 CM表型，包括规定条件下的心室、心房和起搏器CM。因此，MMP 代表了理想的治疗候选物，以在细胞分化后最大化心源性分化效率， 移植，以便用自体CM的供应重新填充梗塞的心脏区域。在 同时，MMP避免了与免疫排斥、肿瘤形成和 回复到另一种表观遗传前体。目的1包括体外研究， 表征MMP（包括发育起源、表面标志物和增殖潜力）， 使用新的排序方法获得所需的CM群体。目标2旨在确定 microRNA和转录因子网络介导的谱系承诺的机制 MMP和MMP的潜在心脏电位受miR-128调节。最后，目标3侧重于 基质金属蛋白酶细胞片移植对小鼠和猪心肌梗死后心功能的影响 模型实验将检查MMP的体内细胞命运，并确定任何有益的效果， 这是由缺血条件下的细胞移植和功能整合引起的。这些研究将提供 在基础心脏发育生物学和基于细胞的再生医学方面的新见解。这 这种方法为新兴的个性化医疗领域带来了巨大的希望，并强烈支持 从人咬肌中获得并在体外扩增的自体MMP将用于 作为CM的主要来源，其将对MI后患者的治疗非常有效。