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)
基本信息
- 批准号:9332765
- 负责人:
- 金额:$ 44.98万
- 依托单位:
- 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:2017-02-06 至 2021-01-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAlpha CellAnimal ModelAnimalsAutologousBiological ProcessBlood flowCardiacCardiac MyocytesCardiovascular systemCause of DeathCell Differentiation processCell TransplantationCellsChromatinClinicalDataDevelopmentDevelopmental BiologyEFRACEngraftmentEpigenetic ProcessFamily suidaeFibrosisGene ExpressionGene Expression ProfileGeneticHarvestHeartHeart AtriumHeart failureHumanHypertrophyIn VitroKnockout MiceLaboratoriesLeftLimb structureMandibleMasseter MuscleMediatingMicroRNAsMiniature SwineModelingMotorMusMuscleMyocardial InfarctionMyocardial IschemiaMyocardial dysfunctionMyocardiumOutcomeOverlapping GenesPacemakersPatientsPhenotypePopulationProcessRegenerative MedicineRegulationRiskSafetySecondary toSeriesSkeletal MuscleSomatic CellSorting - Cell MovementSourceStem cellsSurfaceTechniquesTestingTimeTissuesTransplantationTreatment EfficacyVentricularbasecardiogenesiscoronary artery occlusiondesigneffective therapyexperimental studyheart cellheart functionimplantationimprovedin vivoinnovationinsightinterstitialmotor disordermyocardial damagemyogenesisnerve supplynovelpersonalized medicineprogenitorregenerative therapyrepairedrestorationsatellite cellskeletaltargeted treatmenttherapeutic candidatetranscription factortransdifferentiationtumor
项目摘要
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.
抽象的
心肌梗塞 (MI) 是由于心脏血流不足而导致的,并导致最终损失
心肌细胞(CM)。心肌梗死及其相关并发症是全世界死亡的主要原因。这
寻找能够修复或替代丢失的 CM 的再生疗法仍然是一项艰巨的挑战。这
最重要的问题是难以获得可行的替代细胞。异源来源没有吸引力
由于免疫排斥的可能性。从患者受损的心脏中采集祖细胞是
具有侵入性并造成严重风险。对其他自体来源的体细胞进行重编程可能会导致
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) 细胞具有共同的起源并具有重叠的基因
与心肌的表达模式。 MMP 可以从容易接近的咬肌中分离出来
没有下颌运动功能障碍,我们的初步数据表明,MMP 的产率最高
与肢体肌肉祖细胞相比,CM 分化。重要的是,MMP 可以产生功能性
CM 表型包括特定条件下的心室、心房和起搏器 CM。因此,MMP
代表了细胞后最大化心源性分化效率的理想治疗候选者
移植,以便用自体 CM 重新填充梗死的心脏区域。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。目标 1 包括体外研究以分离和
表征 MMP(包括发育起源、表面标记和增殖潜力),以便
使用新颖的分类方法获得所需的 CM 群体。目标 2 旨在确定
microRNA和转录因子网络介导谱系承诺的机制
MMP 和 MMP 受 miR-128 调节的潜在心脏电位。最后,目标 3 重点关注
植入 MMP 衍生细胞片对小鼠和猪 MI 心脏功能的影响
模型。实验将检查 MMP 的体内细胞命运并确定任何有益的影响
缺血条件下细胞植入和功能整合的结果。这些研究将提供
基础心脏发育生物学和细胞再生医学的新见解。这
该方法为新兴的个性化医疗领域带来了巨大的希望,并大力支持
从人类咬肌中采集并在体外扩增的自体 MMP 可能会发挥作用
作为 CM 的主要来源,对治疗 MI 后患者非常有效。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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W Sean Davidson其他文献
シンポジウム3:日本における原発性高脂血症の現状 家族性高コレステロール血症の診断および治療の課題.
研讨会3:日本原发性高脂血症的现状:家族性高胆固醇血症的诊断和治疗问题。
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
Kuniko Okumura-Noji;Toshihiko Usami;Giorgio Cavigiolio;Rong Huang;W Sean Davidson;Shinji Yokoyama;Maki Tsujita.;Yamada M;野原 淳 - 通讯作者:
野原 淳
Characterization of ion-exchange column fractionated human and mouse apoA-I subfractions.
离子交换柱分级分离的人和小鼠 apoA-I 亚组分的表征。
- DOI:
- 发表时间:
2011 - 期刊:
- 影响因子:0
- 作者:
Kuniko Okumura-Noji;Toshihiko Usami;Giorgio Cavigiolio;Rong Huang;W Sean Davidson;Shinji Yokoyama;Maki Tsujita. - 通讯作者:
Maki Tsujita.
KCNJ5 mutations in aldosterone- and cortisol secreting adrenal adenomas.
醛固酮和皮质醇分泌性肾上腺腺瘤中的 KCNJ5 突变。
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:2
- 作者:
Kuniko Okumura-Noji;Toshihiko Usami;Giorgio Cavigiolio;Rong Huang;W Sean Davidson;Shinji Yokoyama;Maki Tsujita.;Yamada M - 通讯作者:
Yamada M
W Sean Davidson的其他文献
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{{ truncateString('W Sean Davidson', 18)}}的其他基金
The structural basis for cholesterol esterification in human plasma
人血浆中胆固醇酯化的结构基础
- 批准号:
10450679 - 财政年份:2020
- 资助金额:
$ 44.98万 - 项目类别:
The structural basis for cholesterol esterification in human plasma
人血浆中胆固醇酯化的结构基础
- 批准号:
10667541 - 财政年份:2020
- 资助金额:
$ 44.98万 - 项目类别:
The molecular basis for the role of apolipoprotein A-II in cholesterol and triglyceride metabolism
载脂蛋白 A-II 在胆固醇和甘油三酯代谢中作用的分子基础
- 批准号:
10533294 - 财政年份:2020
- 资助金额:
$ 44.98万 - 项目类别:
The structural basis for cholesterol esterification in human plasma
人血浆中胆固醇酯化的结构基础
- 批准号:
10206267 - 财政年份:2020
- 资助金额:
$ 44.98万 - 项目类别:
The molecular basis for the role of apolipoprotein A-II in cholesterol and triglyceride metabolism
载脂蛋白 A-II 在胆固醇和甘油三酯代谢中作用的分子基础
- 批准号:
10096569 - 财政年份:2020
- 资助金额:
$ 44.98万 - 项目类别:
The structural basis for cholesterol esterification in human plasma
人血浆中胆固醇酯化的结构基础
- 批准号:
10028460 - 财政年份:2020
- 资助金额:
$ 44.98万 - 项目类别:
The molecular basis for the role of apolipoprotein A-II in cholesterol and triglyceride metabolism
载脂蛋白 A-II 在胆固醇和甘油三酯代谢中作用的分子基础
- 批准号:
10318588 - 财政年份:2020
- 资助金额:
$ 44.98万 - 项目类别:
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