Cardiac conduction system cells and uses thereof
First Claim
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1. A method of identifying a population of non-contracting cardiac pacemaking cells comprising:
- transfecting a stem cell with an expression construct comprising a GATA-6 regulatory element operably linked to a coding sequence for a surrogate marker, wherein the promoter element is selectively active in cardiomyocytes that display an If pacemaking current.
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Abstract
Isolation and amplification of cardiac pacemaking/conduction system cells and development of a pacemaking/conduction system in vitro using the expression of surrogate expression markers. Use of markers to identify and select for clusters of pacemaking “nodes” that are functionally coupled with adjacent contracting regions and generation of cell populations displaying electrical properties characteristic of specialized pacemaking/conducting cardiac myocytes for modeling the cardiac conduction system, testing of pharmaceuticals and for transplantation.
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Citations
45 Claims
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1. A method of identifying a population of non-contracting cardiac pacemaking cells comprising:
transfecting a stem cell with an expression construct comprising a GATA-6 regulatory element operably linked to a coding sequence for a surrogate marker, wherein the promoter element is selectively active in cardiomyocytes that display an If pacemaking current. - View Dependent Claims (2, 3, 4, 5, 6)
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7. A method of identifying cardiac conducting system cells in a population of pluripotent cells comprising detecting expression of a developmental stage specific protein selected from the group consisting of:
- GATA6, minK, and combinations thereof, in the pluripotent cells
- View Dependent Claims (8, 9, 10)
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11. A method of selecting pacemaking cells having a characteristic of sinoatrial node cells comprising:
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transfecting a stem cell with an expression construct encoding a selectable marker under the transcriptional control of a regulatory element derived from a GATA-6 promoter;
selecting a population of cells expressing a selectable marker; and
expanding the population of cells in vitro, thereby generating an enriched population cells having a characteristic of sinoatrial node cells. - View Dependent Claims (12, 13, 14, 15, 16)
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17. A model system for determining a pharmacologic effect of a compound on cells of a mammalian cardiac conducting system comprising a population of embryonic stem cells that have been selected for expression of a developmental stage specific protein selected from a group consisting of:
- GATA6, minK, and combinations thereof.
- View Dependent Claims (18, 19, 20, 21, 22, 23)
- 24. A process for isolation and enrichment of cardiac pacemaking cells from stem cell populations comprising transforming a population of stem cells with an expression construct encoding a surrogate marker for GATA6 expression.
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32. A population of stem cells that have been differentiated and selected for expression of a PCS protein selected from the group consisting of:
- GATA6, minK, connexin 40, and combinations thereof.
- View Dependent Claims (33, 34, 35)
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36. A method of treating cardiac arrhythmias comprising transplantation into a heart of a population of stem cells that have been selected for expression of a PCS protein selected from a group consisting of:
- GATA6, minK, connexin 40, and combinations thereof.
- View Dependent Claims (37, 38, 39, 40)
- 41. A method of inducing phenotypic differentiation in a stably maintained nodal cell population by culturing the cell population in a differentiation medium.
Specification