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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：
10471189
负责人：
Hina W Chaudhry
金额：
$ 70.07万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471189
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 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 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 regeneration function 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.

项目总结