Human CDX2 Cells and Cardiac Repair

人类 CDX2 细胞与心脏修复

• 批准号: 10221044
• 负责人: Hina W Chaudhry
• 金额: $ 70.2万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-21 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221044
• 关键词: Address; Adult; Allogenic; Animal Model; Blood Circulation; Blood Vessels; CDX2 gene; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Differentiation process; Cell Surface Proteins; Cell Therapy; Cell membrane; Cell surface; Cells; Clinical; Collaborations; Consultations; Data; Development; Endothelial Cells; Endothelium; Engraftment; Exhibits; Fetus; Gene Expression Profiling; Genes; Genomics; Goals; Growth; Harvest; Heart; Heart Diseases; Heart Injuries; Histocompatibility; Home; 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; Population; 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; fetus cell; heart function; human embryonic stem cell; immunogenic; in vivo; injured; insight; male; mouse model; myocardial injury; novel; primitive cell; recombinase-mediated cassette exchange; regeneration function; repaired; stem; stem cell therapy; stem cells; stemness; transcriptome; transcriptome sequencing; transcriptomics; trophoblast stem cell

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.

项目概要 已知胎儿来源的胎盘细胞在怀孕期间进入母体循环，并且可能持续存在 母体组织几十年来一直是微嵌合体。我们已经报道过，胎儿细胞选择性地归巢于受伤的细胞 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 母体心脏损伤区的多能胎儿细胞。在体外，从母体心脏分离胎儿细胞 概括这些分化途径，形成血管并自发跳动 心肌细胞以不依赖融合的方式进行。母体中胎儿细胞的显着比例（~40%） 心脏表达尾部相关同源盒2 (Cdx2)，先前与滋养层干细胞相关。 利用 cre-lox 技术进行谱系追踪，我们现已证明可以从 妊娠末期胎盘，可在体外形成跳动的心肌细胞和血管细胞。此外，他们 表现出转录组特征，表明其具有逃避宿主免疫监视的能力。蛋白质组学 与 ES 细胞相比，这些细胞的研究揭示了独特的生长、存活和归巢优势，但 保留 ES 细胞的“干性”特性。因此转录组和蛋白质组分析揭示 有助于开发同种异体细胞治疗方法的理想品质。在进一步支持中 为了实现这一目标，我们已经证明 Cdx2 细胞能够稳健且特异性地归巢于梗塞心脏 注射到尾静脉后，在体内分化为心肌细胞和血管。核磁共振成像 表现出显着且持续的收缩性增强（PNAS 修订稿）。我们 还表明 CDX2 细胞可以从人类足月胎盘中分离出来。我们的最终目标是翻译 这些研究用于临床，我们提出了利用最尖端技术的三个目标 科学来实现这一目标。在目标 1 中，我们将发现人类 CDX2 细胞的独特细胞表面标记 通过转录组/蛋白质组分析并探索其归巢机制。在目标 2 中，我们力求理解 这些细胞的免疫学特性，以帮助同种异体人类细胞疗法的发展。 我们还将确定他们形成畸胎瘤的倾向。在目标 3 中，我们将确认 CDX2 细胞也能提供 心肌梗死（MI）后在体外和体内产生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增强心肌 MI 后的功能，因为这将帮助我们设计治疗策略。