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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妊娠期间进入母体循环，并可能持续存在。母体组织作为微嵌合体存在了几十年我们已经报道过胎儿细胞选择性地归巢于受伤的母体心肌并分化成不同的心脏谱系。使用增强型绿色荧光蛋白（eGFP）标记的胎儿，我们证明了植入和心脏分化的母体心脏损伤区的多能胎儿细胞。在体外，从母体心脏中分离的胎儿细胞重演这些分化途径，形成维管并自发搏动以不依赖融合的方式与心肌细胞融合。母体中有相当大比例（约40%）的胎儿细胞心脏表达Caudal相关同源框2（Cdx 2），以前与滋养层干细胞相关。利用cre-lox技术进行谱系追踪，我们现在已经证明Cdx 2细胞可以从妊娠末期胎盘，并能在体外形成搏动的心肌细胞和血管细胞。而且他们表现出转录组特征，表明有能力逃避宿主免疫监视。蛋白组与ES细胞相比，这些细胞的研究揭示了不同的生长，存活和归巢优势，但保留胚胎干细胞的“干性”特性。因此，转录组学和蛋白质组学分析揭示了所需的品质，可以帮助开发同种异体细胞治疗方法。为进一步支持为了达到这个目的，我们已经证明Cdx 2细胞可以稳定而特异地归巢于梗死的心脏注射到尾静脉后，在体内分化为心肌细胞和血管。MRI 显示出显著和持续的收缩性增强（PNAS修订稿）。我们还表明CDX 2细胞可以从人足月胎盘中分离。我们的最终目标是翻译这些研究用于临床，我们提出了三个目标，利用最前沿的技术，科学是为了实现这一点。在目标1中，我们将发现人CDX 2细胞的独特细胞表面标志物，通过转录组/蛋白质组分析，探索它们的归巢机制。在目标2中，我们寻求理解这些细胞的免疫学特性，以帮助开发同种异体人细胞疗法。我们还将确定他们形成畸胎瘤的倾向。在目标3中，我们将证实CDX 2细胞也提供心肌梗死（MI）后在体外和体内培养功能性心肌细胞和血管细胞，在野生型和NOD/SCID小鼠中诱导。我们还将测试这些细胞是否能增强心肌这将有助于我们设计治疗策略。