Electrophysiologically mature cardiomyocytes and methods for making same

Abstract

Methods to prepare electrophysiology mature cells from immature cells are provided, without the need for genetic manipulation.

1 . A method for inducing expression of the Kir2.1 gene in a cell lacking functional Kir2.1 gene expression in the absence of genetic manipulation of the cell, comprising administering to the cell an effective amount of electrical pacing, thereby inducing expression of Kir2.1 gene in the cell. 
     
     
         2 . A method for inducing an electrophysiologically mature phenotype in a cell that is not terminally differentiated or electrophysiologically mature, comprising administering to the cell an effective amount of electrical pacing, thereby inducing the electrophysiologically mature phenotype in the cell. 
     
     
         3 . A method for preparing an electrophysiologically mature cardiomyocyte in a cell that is not terminally differentiated or electrophysiologically mature, comprising administering to the cell an effective amount of electrical pacing, thereby preparing an electrophysiologically mature cardiomyocyte. 
     
     
         4 . The method of  claim 3 , wherein the electrophysiologicially mature phenotype comprises a cardiomyocyte that expresses one or more of an increase in one or more of the contractile proteins selected from MHCα, MHCβ, MLC2a, MLC2v and cardiac ion channel pump proteins. 
     
     
         5 . The method of  claim 3 , wherein the method excludes genetic manipulation of the cell to enhance or increase Kir2.1 expression. 
     
     
         6 . The method of  claim 2 , wherein the cell comprises one or more of an embryonic stem cell, a pluriopotent stem cell, an embryoid body, a mesodermal cardiosphere or an induced pluripotent stem cell. 
     
     
         7 . The method of  claim 2 , wherein the electrophysiologically mature cardiomyocyte produced by the method expresses upregulated contractile proteins. 
     
     
         8 . The method of  claim 3 , wherein the electrophysiologically mature cardiomyocyte produced by the method expresses upregulated contractile proteins. 
     
     
         9 . The method of  claim 2 , wherein the cell that is not electrophysiologically mature cardiomyocyte comprises a cardiac cell of the group of a ventricular cell or an atrial cell. 
     
     
         10 . The method of  claim 3 , wherein the cell that is not electrophysiologically mature cardiomyocyte comprises a cardiac cell of the group of a ventricular cell or an atrial cell. 
     
     
         11 . The method of  claim 2 , wherein the electrical pacing comprises a pulsed electrical current of from about 2.0 to about 3.0 v/cm for about 2 msec to about 8 msec, at a width of about 0.5 HZ to about 1.5 HZ. 
     
     
         12 . An isolated cell produced by the method of  claim 2 , wherein the cell is electrophysically mature and is not terminally differentiated. 
     
     
         13 . An expanded population substantially homogenous population of cells of  claim 12 . 
     
     
         14 . A clonal population of cells of  claim 13 . 
     
     
         15 . A composition comprising the isolated cell of  claim 12  and a carrier. 
     
     
         16 . A composition comprising an expanded population of  claim 13  and a carrier. 
     
     
         17 . A composition comprising an expanded population of  claim 14  and a carrier. 
     
     
         18 . The composition of  claim 15 , wherein the carrier is one or more of a pharmaceutically acceptable carrier or a biocompatible scaffold. 
     
     
         19 . A method for treating a subject in need thereof, comprising administering to the subject an effective amount of the cell of  claim 12 . 
     
     
         20 . A method for treating a subject in need thereof, comprising administering to the subject an effective amount of the clonal population of  claim 14 .