Methods of cardiac repair

a cardiac and ventricular technology, applied in the field of cardiac repair, can solve the problems of deterioration of ventricular function, ventricular function, ventricular function, heart failure, etc., and achieve the effects of increasing cardiomyocyte cell cycle activation, increasing cardiomyocyte proliferation, and increasing cardiomyocyte formation

Inactive Publication Date: 2017-11-23
MT SINAI SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]Provided herein is a composition comprising a population of cells and a pharmaceutically acceptable carrier for increasing cardiomyocyte formation, increase cardiomyocyte proliferation, increase cardiomyocyte cell cycle activation, increase mitotic index of cardiomyocytes, increase myofilament density, increase borderzone wall thickness, or a combination thereof, wherein said cells express one or more markers identified in Table 2 or in FIG. 5C. In one embodiment, the cells are derived from placenta. In another embodiment, the cells are progenitor cells or stem cells. In another embodiment, the cells express Cdx2, Cd9, Eomes, CD34, CD31, c-kit, or a combination thereof. In another embodiment, the cells express Cdx2 and Cd9.
[0018]In various embodiments, the cell population increases cardiomyocyte formation, increases cardiomyocyte proliferation, increases cardiomyocyte cell cycle activation, increases mitotic index of cardiomyocytes, increases myofilament density, increases borderzone wall thickness, or a combination thereof.
[0020]In one embodiment, the composition increases cardiomyocyte formation, increase cardiomyocyte proliferation, increase cardiomyocyte cell cycle activation, increase mitotic index of cardiomyocytes, increase myofilament density, increase borderzone wall thickness, or a combination thereof, when administered to a subject.
[0022]Provided herein is a composition including a population of Cdx2 cells and a pharmaceutically acceptable carrier for the preparation of a medicament to increase cardiomyocyte formation, increase cardiomyocyte proliferation, increase cardiomyocyte cell cycle activation, increase mitotic index of cardiomyocytes, increase myofilament density, increase borderzone wall thickness, or a combination thereof. In one embodiment, the cells are derived from placenta. In another embodiment, the cells are progenitor cells or stem cells. In another embodiment, the cells express Cdx2, and further express Cd9, Eomes, CD34, CD31, c-kit or a combination thereof. In another embodiment, the cells express Cdx2 and Cd9.
[0025]In one embodiment, the composition increases cardiomyocyte formation, increases cardiomyocyte proliferation, increases cardiomyocyte cell cycle activation, increases mitotic index of cardiomyocytes, increases myofilament density, increases borderzone wall thickness, or a combination thereof, when administered to a subject.
[0027]A composition including a population of Cdx2 cells and a pharmaceutically acceptable carrier to increase cardiomyocyte formation, increase cardiomyocyte proliferation, increase cardiomyocyte cell cycle activation, increase mitotic index of cardiomyocytes, increase myofilament density, increase borderzone wall thickness, or a combination thereof. In one embodiment, the cells are derived from placenta. In another embodiment, the cells are progenitor cells or stem cells. In another embodiment, the cells express Cdx2, and further express Cd9, Eomes, CD34, CD31, c-kit, or a combination thereof. In another embodiment, the cells express Cdx2 and Cd9.

Problems solved by technology

Myocardial infarctions result in an immediate depression in ventricular function and the infarctions may expand, thereby causing ventricular remodeling.
In many patients, progressive myocardial infarct expansion and ventricular remodeling leads to deterioration of ventricular function and heart failure.
Within seconds of a myocardial infarction, the under-perfused myocardial cells no longer contract, leading to abnormal wall motion, high wall stresses within and surrounding the infarct, and depressed ventricular function.
These high stresses eventually kill or severely depress function in the still viable myocardial cells.
The consequences of MI may be often severe and disabling.

Method used

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Examples

Experimental program
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Effect test

example 1

Fetal Cells Home to and Engraft in Injured Maternal Myocardium

[0189]Wild-type (WT) virgin female mice, age 3-6 months, were crossed with heterozygous eGFP transgenic male mice. The female mice underwent ligation of the left anterior descending (LAD) artery in order to induce an anterolateral myocardial infarction (MI) at gestation day 12 (FIG. 1A). This results in approximately 50% left ventricular infarction. In accordance with Mendelian autosomal inheritance, approximately 50% of embryos were eGFP+.

[0190]Initially, we quantified eGFP expression in injured maternal hearts relative to sham-operated pregnant mice and controls in which no injury was induced. Post-partum females were sacrificed at 1 or 2 weeks post-MI. Total DNA was extracted from each total heart and eGFP expression analyzed according to the methods described by Pfaffl, 2001 (FIG. 1B). Experimental infarcted hearts harvested at 1 week post-MI contained 120 times more eGFP than controls (p=0.0003) and 20 times more eGF...

example 2

Fetal Cells Adopt Diverse Cardiac Lineages In Vivo

[0191]In a separate group of infarcted and control mice, immunofluorescence analysis with confocal microscopy was utilized to detect eGFP+ cells in ventricular tissue sections of maternal hearts at various time points subsequent to myocardial injury (FIG. 1B and data not shown). EGFP+ cells were noted in infarct zones and peri-infarct zones of infarcted maternal hearts at 1, 2, 3, or 4 weeks post-MI (data not shown and Table 1A). Negligible numbers of eGFP cells were noted in non-infarct zones of the infarcted maternal hearts (Table 1B).

[0192]We further sought to determine whether the eGFP+ cells were differentiating into more mature cardiac cells as we noted a decrease in nuclear to cytoplasmic ratio with an increase in post-injury time (data not shown). Briefly, ventricular sections from maternal hearts analyzed at 1, 2, 3, and 4 weeks post-injury illustrated eGFP+ cells engrafting within infarct and peri-infarct zones. Fetal cells...

example 3

Fetal Cells Isolated From Injured Maternal Hearts Differentiate To Endothelial Cells, Smooth Muscle Cells, and Spontaneously Beating Cardiomyocytes In Vitro

[0195]We next used fluorescence activated cell sorting (FACS) to isolate fetal eGFP+ cells that had homed to maternal hearts and analyzed their in vitro behavior. When plated on CMFs, we noted clonal expansion of the fetal cells, their differentiation into smooth muscle cells and endothelial cells, and the formation of vascular structures (data not shown). Other cellular phenotypes, some of which have the appearance of neuronal cells, were also observed in these in vitro experiments with CMFs (data not shown).

[0196]Briefly, in vitro analysis of fetal cells isolated from maternal hearts demonstrated clonal expansion on CMFs. 14 days after plating, vascular tube formation was noted in a 3-dimensional collagen matrix. Fetal cells isolated from maternal hearts and plated on CMFs underwent differentiation into smooth muscle cells (a-S...

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Abstract

Provided herein is a new method to isolate and expand cardiac progenitor / stem cells from a placenta, which produces a cell population enriched in multipotent functional progenitor / stem cells. Cardiac progenitor / stem cells isolated by this method maintain their self-renewal character in vitro and differentiate into normal cells in myocardium, including cardiomyocytes, endothelial cells, and smooth muscle cells, after transplantation into ischemic hearts. Also provided in this application are substantially pure populations of multipotent cardiac progenitor / stem cells, and their use to treat and prevent diseases and injuries, including those resulting from myocardial infarction. A model for assessing the potential of cardiac stem cells for treatment of myocardial infarction is also provided.

Description

CROSS-REFERENCE[0001]This application is a Continuation of U.S. application Ser. No. 13 / 671,396, filed Nov. 7, 2012, which claims the benefit of U.S. Provisional Application No. 61 / 556,700, filed Nov. 7, 2011, which application is incorporated herein by reference in its entirety.STATEMENT OF FEDERAL FUNDING[0002]Embodiments of the present application were made, in part, with U.S. government support under NHLBI (R01-HL 088255) awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Heart failure is the leading cause of hospitalization in the US and heart disease remains the number one killer in the industrialized world. Each year over 1.1 million Americans have a myocardial infarction (“MI”), typically caused by a heart attack, with median survival after onset only 1.7 years in men and 3.2 years in women. Typically, 225,000 people suffering MI die before reaching the hospital.[0004]Myocardial infarctions result...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/50A61K35/12
CPCA61K35/12A61K35/50A61P9/00
Inventor CHAUDHRY, HINA W.
Owner MT SINAI SCHOOL OF MEDICINE
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