Comprehensive in vivo MRI of mouse embryonic stem cell myocardial engraftment

小鼠胚胎干细胞心肌移植的综合体内 MRI

• 批准号: 8284427
• 负责人: PHILLIP CHUNG-MING YANG
• 金额: $ 39.31万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284427
• 关键词: Address; Award; Biological Process; Cardiac Myocytes; Cell Survival; Cell Transplants; Cells; Clinical; Complex; Congestive Heart Failure; Data; Detection; Development; Engraftment; Epidemic; Evaluation; Hindlimb; Human; International; Investigation; K-18 conjugate; Label; Lead; Magnetic Resonance Imaging; Manganese; Manuscripts; Methodology; Methods; Modality; Molecular; Monitor; Mus; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Organ; Pluripotent Stem Cells; Public Health; Publications; Publishing; Regenerative Medicine; Reporter Genes; Research; Research Proposals; Resolution; Science; Signal Transduction; Skin; Stem Cell Research; Stem cells; System; Techniques; Technology; Teratoma; Tissues; Translations; Transplantation; Treatment Efficacy; abstracting; career; clinical application; design; embryonic stem cell; functional restoration; genetically modified cells; human embryonic stem cell; in vivo; injured; innovation; meetings; novel; nuclear reprogramming; public health relevance; research study; restoration; stem cell biology

DESCRIPTION (provided by applicant): ABSTRACT: This proposal is submitted to request a continuation of the research conducted during the K18 Career Enhancement Award in Stem Cell Research (02/01/07-01/31/09). In this proposed research, further investigation to enhance in vivo cellular and molecular MRI of mESC survival and proliferation (teratoma formation) following transplantation into the myocardium is described. The rationale of this research comes from a fundamental notion underlying regenerative medicine: the transplanted cells must survive to trigger a complex cascade of biological processes to regenerate and restore the injured myocardium permanently. Although MRI has become one of the predominant modalities to track ex vivo labeled cells and to evaluate functional restoration of the recipient myocardium, definitive information on cellular viability and proliferation can not be assessed in vivo. This research study proposes to develop robust in vivo MRI methods to detect and quantitate viable cells following delivery into the injured myocardium, which will enable accurate assessment of therapeutic efficacy of regenerative medicine while also monitor for potential teratoma formation. Novel MRI methods, innovative cellular and molecular techniques, and an array of established methodologies have been integrated to study 3 hypothesis driven Specific Aims: Specific Aim 1 Manganese (Mn2+)-guided in vivo cellular MRI will enable longitudinal evaluation of mESC survival following transplantation into the injured murine myocardium. Specific Aim 2 Reporter gene (RG)-guided in vivo molecular MRI of genetically engineered cells will enable longitudinal evaluation of mESC survival following transplantation into the injured murine myocardium. Specific Aim 3 Optimal quantity of viable mESC will restore the injured myocardium and minimize teratoma formation. This research proposal outlines a rigorous study of in vivo cellular and molecular MRI to address a fundamental challenge in regenerative medicine: mESC survival and abnormal proliferation following delivery into the injured myocardium. This proposal has been designed to advance in vivo cellular and molecular MRI methods with demonstrated proof-of-concept. High spatial and temporal resolution of MRI will be optimized with viability-specific cellular and molecular signal amplification techniques to generate quantitative data on cell survival and teratoma formation following transplantation into target organ. Upon successful conclusion of this research, a comprehensive MRI platform will be developed to quantitate cellular viability, proliferation, and myocardial restoration. Cross-disciplinary application of this nascent technology will provide enabling technology to assess fundamental stem cell biology of any transplanted cell and evaluate recipient tissue function of any human organ. Public Health Relevance Statement (provided by applicant): Stem cell research stands at a critical juncture. Recent development in nuclear reprogramming of human skin cells to generate pluripotent stem cells and directed differentiation of human embryonic stem cells into cardiomyocyte may lead to significant clinical breakthrough in the treatment of congestive heart failure, a public health epidemic. The proposed in vivo MRI system represents a dedicated platform to enable systematic translation of basic stem cell science to clinical application.

描述（由申请人提供）： 摘要：该提案提交要求继续在干细胞研究（02/01/07-01/31/09）的K18职业增强奖中进行的研究继续进行。在这项拟议的研究中，描述了进一步的研究，以增强移植到心肌后MESC存活和增殖的体内细胞和分子MRI（畸胎瘤形成）。这项研究的基本原理来自再生医学的基本概念：移植的细胞必须生存以触发复杂的生物过程级联，以永久性地再生和恢复受伤的心肌。尽管MRI已成为跟踪离体标记细胞并评估受体心肌功能恢复的主要模式之一，但无法在体内评估有关细胞活力和增殖的明确信息。这项研究建议开发出强大的体内MRI方法，以检测和定量进入受伤的心肌后的活细胞，这将使能够准确评估再生医学的治疗功效，同时还可以监测潜在的畸胎瘤形成。新颖的MRI方法，创新的细胞和分子技术以及一系列已建立的方法已经整合到研究3个假设驱动的特定目标：特定目标1锰（MN2+） - 在体内细胞MRI中引导，启用了MESC的纵向评估，可对MESC进行纵向评估。特定的AIM 2报告基因（RG）在基因工程细胞的体内MRI中指导，将在移植到受伤的鼠心肌中后对MESC存活进行纵向评估。特定的目标3最佳量的可行MESC将恢复受伤的心肌并最大程度地减少畸胎瘤的形成。这项研究提案概述了对体内细胞和分子MRI的严格研究，以解决再生医学中的基本挑战：MESC生存和传递到受伤的心肌后的异常增殖。该建议旨在推进具有概念验证证明的体内细胞和分子MRI方法。 MRI的高空间和时间分辨率将通过可行性特异性细胞和分子信号扩增技术进行优化，以生成有关细胞存活和畸胎瘤形成后形成的定量数据。在这项研究的成功结束后，将开发一个全面的MRI平台，以量化细胞活力，增殖和心肌恢复。这种新生技术的跨学科应用将提供能够评估任何移植细胞的基本干细胞生物学，并评估任何人体器官的受体组织功能。 公共卫生相关性声明（由申请人提供）：干细胞研究处于关键时刻。人类皮肤细胞核重编程的最新发展以产生多能干细胞并将人类胚胎干细胞分化为心肌细胞，可能会导致在治疗充血性心力衰竭的临床突破，这是一种公共卫生的流行。所提出的体内MRI系统代表了一个专门的平台，可以将基本干细胞科学系统转换为临床应用。

项目成果

Graphite oxide nanoparticles with diameter greater than 20 nm are biocompatible with mouse embryonic stem cells and can be used in a tissue engineering system.

• DOI: 10.1002/smll.201303133
• 发表时间: 2014-04-24
• 期刊: SMALL
• 影响因子: 13.3
• 作者: Wang, I-Ning E.;Robinson, Joshua T.;Do, Grace;Hong, Guosong;Gould, Danny R.;Dai, Hongjie;Yang, Phillip C.
• 通讯作者: Yang, Phillip C.

Apelin enhances directed cardiac differentiation of mouse and human embryonic stem cells.

• DOI: 10.1371/journal.pone.0038328
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wang IN;Wang X;Ge X;Anderson J;Ho M;Ashley E;Liu J;Butte MJ;Yazawa M;Dolmetsch RE;Quertermous T;Yang PC
• 通讯作者: Yang PC

Theranostic effect of serial manganese-enhanced magnetic resonance imaging of human embryonic stem cell derived teratoma.

• DOI: 10.1002/mrm.23262
• 发表时间: 2012-08
• 期刊: MAGNETIC RESONANCE IN MEDICINE
• 影响因子: 3.3
• 作者: Chung, Jaehoon;Dash, Rajesh;Kee, Kehkooi;Barral, Joelle K.;Kosuge, Hisanori;Robbins, Robert C.;Nishimura, Dwight;Reijo-Pera, Renee A.;Yang, Phillip C.
• 通讯作者: Yang, Phillip C.

Apelin-13 infusion salvages the peri-infarct region to preserve cardiac function after severe myocardial injury.

• DOI: 10.1016/j.ijcard.2016.07.263
• 发表时间: 2016-11-01
• 期刊: INTERNATIONAL JOURNAL OF CARDIOLOGY
• 影响因子: 3.5
• 作者: Chung, Wook-Jin;Cho, Ahryon;Byun, Kyunghee;Moon, Jeongsik;Ge, Xiaohu;Seo, Hye-Sun;Moon, Ejung;Dash, Rajesh;Yang, Phillip C.
• 通讯作者: Yang, Phillip C.

Molecular Imaging of Stem Cell Transplantation in Myocardial Disease.

心肌疾病干细胞移植的分子成像。

• DOI: 10.1007/s12410-009-9001-4
• 发表时间: 2010
• 期刊: Current cardiovascular imaging reports
• 影响因子: 0.9
• 作者: Chung,Jaehoon;Yang,PhillipC
• 通讯作者: Yang,PhillipC