Human CDX2 Cells and Cardiac Repair

人类 CDX2 细胞与心脏修复

基本信息

批准号：
10686025
负责人：
Hina W Chaudhry
金额：
$ 71.42万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-21 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686025
关键词：
Address Adult Allogenic Animal Model Blood Vessels CDX2 gene Cardiac Cardiac Myocytes Cardiovascular system Cell Differentiation process Cell Separation Cell Surface Proteins Cell Therapy Cell membrane Cell surface Cells Circulation Clinical Collaborations Consultations Cre lox recombination system Data Development Endothelial Cells Endothelium Engraftment Exhibits Fetus Gene Expression Profiling Genes Genomics Goals Growth Harvest Heart Heart Diseases Heart Injuries Histocompatibility Home Homeobox Homing Human Immune Immunologic Surveillance Immunologics In Vitro Injections Injury Intravenous Laboratories Lead Magnetic Resonance Imaging Manuscripts Membrane Proteins Methods Mus Myocardial Myocardial Infarction Myocardium NOD/SCID mouse Nature Pathway interactions Peptide Sequence Determination Placenta Pregnancy Property Proteome Proteomics Protocols documentation Regenerative Medicine Reporting Science Seminal Signal Pathway Signal Transduction Site Smooth Muscle Myocytes Tail Techniques Technology Teratoma Testing Therapeutic Tissues Translating Tube Validation Veins base blastocyst cardiac regeneration cardiac repair cell type design embryonic protein embryonic stem cell enhanced green fluorescent protein experience fetal fetal stem cell fetus cell heart function human embryonic stem cell immunogenic in vivo injured insight intravenous administration male mouse model myocardial injury novel primitive cell repaired stem stem cell therapy stem cells stemness transcriptome transcriptome sequencing transcriptomics trophoblast stem cell

项目摘要

Project Summary Fetal-derived placenta cells are known to enter the maternal circulation during pregnancy and may persist in maternal tissue for decades as microchimeras. We have reported that fetal cells selectively home to injured maternal myocardium and undergo differentiation into diverse cardiac lineages. Using enhanced green fluorescent protein (eGFP)-tagged fetuses, we demonstrated engraftment and cardiac differentiation of mulitpotent fetal cells in injury zones of maternal hearts. In vitro, fetal cells isolated from maternal hearts recapitulate these differentiation pathways, forming vascular tubes and spontaneously beating cardiomyocytes in a fusion-independent manner. A significant proportion (~40%) of fetal cells in maternal hearts express Caudal-related homeobox2 (Cdx2), previously associated with trophoblast stem cells. Utilizing cre-lox technology for lineage-tracing, we have now shown that Cdx2 cells can be isolated from end-gestation placenta and can form beating cardiomyocytes and vascular cells in vitro. Furthermore, they exhibit a transcriptomic signature that suggests an ability to evade host immune surveillance. Proteomic studies of these cells compared to ES cells reveal distinct growth, survival and homing advantages, but with retention of the `stemness' properties of ES cells. Thus the transcriptomic and proteomic analysis reveal desirable qualities that can aid in the development of an allogeneic cell therapy approach. In further support of this objective, we have demonstrated that Cdx2 cells home robustly and specifically to infarcted hearts upon injection into the tail vein, with differentiation in vivo to cardiomyocytes and blood vessels. MRI demonstrates significant and sustained enhancement of contractility (manuscript in revision at PNAS). We have also shown that CDX2 cells can be isolated from human term placentas. Our final goal is to translate these studies for clinical use, and we propose three aims utilizing the most cutting-edge technologies in science in order to achieve this. In aim 1, we will uncover unique cell surface markers of human CDX2 cells via trancriptome/proteome profiling and explore their homing mechanisms. In aim 2, we seek to understand immunologic properties of these cells in order to aid in the development of allogeneic human cell therapy. We will also ascertain their propensity to form teratomas. In aim 3, we will confirm that CDX2 cells also give rise to functional cardiomyocytes and vascular cells in vitro and in vivo after myocardial infarction (MI) is induced in wild-type and NOD/SCID mice. We will also test whether these cells enhance myocardial function after MI, as this will aid us in designing a therapeutic strategy.

项目摘要已知胎儿来源的胎盘细胞在怀孕期间进入母体循环，可能会持续孕产妇组织数十年是微壳。我们报告说，胎儿细胞有选择地归于受伤母体心肌并将其分化为多种心脏谱系。使用增强的绿色荧光蛋白（EGFP）标记的胎儿，我们证明了植入和心脏分化孕产妇心脏损伤区域中的mulittent胎儿细胞。体外，从母体心脏分离的胎儿细胞概括这些分化途径，形成血管管和自发跳动心肌细胞以融合无关的方式。母体中胎儿细胞的显着比例（〜40％）心脏表达尾骨相关的同源ox2（CDX2），以前与滋养细胞干细胞有关。利用Cre-Lox技术进行谱系追踪，我们现在表明CDX2细胞可以与末端捕获胎盘，可以在体外形成跳动的心肌细胞和血管细胞。此外，他们展示了转录组签名，表明可以逃避宿主免疫监测的能力。蛋白质组学与ES细胞相比，对这些细胞的研究揭示了明显的生长，生存和归巢优势，但是 ES细胞的“茎”特性的保留。因此，转录组和蛋白质组学分析揭示了理想的品质可以帮助开发同种异体细胞疗法。进一步支持在这个目标中，我们已经证明了CDX2细胞可以坚固，专门用于梗塞心脏注射到尾静脉后，体内分化为心肌细胞和血管。 MRI 表现出显着和持续增强的收缩力（在PNA的修订中手稿）。我们还表明，CDX2细胞可以从人术语胎盘中分离出来。我们的最终目标是翻译这些用于临床使用的研究，我们提出了利用最尖端技术的三个目标为了实现这一目标。在AIM 1中，我们将发现人CDX2细胞的独特细胞表面标记通过trancriptom/蛋白质组分析并探索其归巢机制。在AIM 2中，我们试图了解这些细胞的免疫学特性是为了帮助发展同种异体人类细胞疗法。我们还将确定它们形成畸胎瘤的倾向。在AIM 3中，我们将确认CDX2细胞也给出体外和体内心肌梗塞（MI）的体内和体内的功能性心肌细胞（MI）的兴起诱导的野生型和点头/SCID小鼠。我们还将测试这些细胞是否增强心肌 MI之后的功能，因为这将有助于我们设计一种治疗策略。