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Proc Natl Acad Sci U S A. 2019 Jun 11;116(24):11786-11795. doi: 10.1073/pnas.1811827116. Epub 2019 May 20.

Multipotent fetal-derived Cdx2 cells from placenta regenerate the heart.

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Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Advanced Clinical Biosystems Research Institute, Smidt Heart Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
Department of Medicine, Johns Hopkins University, Baltimore, MD 21218.
Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;


The extremely limited regenerative potential of adult mammalian hearts has prompted the need for novel cell-based therapies that can restore contractile function in heart disease. We have previously shown the regenerative potential of mixed fetal cells that were naturally found migrating to the injured maternal heart. Exploiting this intrinsic mechanism led to the current hypothesis that Caudal-type homeobox-2 (Cdx2) cells in placenta may represent a novel cell type for cardiac regeneration. Using a lineage-tracing strategy, we specifically labeled fetal-derived Cdx2 cells with enhanced green fluorescent protein (eGFP). Cdx2-eGFP cells from end-gestation placenta were assayed for cardiac differentiation in vitro and in vivo using a mouse model of myocardial infarction. We observed that these cells differentiated into spontaneously beating cardiomyocytes (CMs) and vascular cells in vitro, indicating multipotentiality. When administered via tail vein to infarcted wild-type male mice, they selectively and robustly homed to the heart and differentiated to CMs and blood vessels, resulting in significant improvement in contractility as noted by MRI. Proteomics and immune transcriptomics studies of Cdx2-eGFP cells compared with embryonic stem (ES) cells reveal that they appear to retain "stem"-related functions of ES cells but exhibit unique signatures supporting roles in homing and survival, with an ability to evade immune surveillance, which is critical for cell-based therapy. Cdx2-eGFP cells may potentially represent a therapeutic advance in allogeneic cell therapy for cardiac repair.


Cdx2; cardiac regeneration; cardiomyocytes; placenta; stem cells

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Conflict of interest statement

Conflict of interest statement: H.W.C. is the founder and an equity holder in VentriNova, Inc. and is the inventor on a pending patent regarding Cdx2 cells and cardiac repair.

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