Compositions and Methods for Improving the Functional Efficacy of Stem Cell-Derived Cardiomyocytes

Abstract

An isolated stem cell that has been modified to provide, enhance orcontain the functional characteristics of the sarcoplasmic reticulum (SR). The isolated stem cells are modified in one or more of the following manners: by expressing a calcium channel protein; by expressing a calcium pump protein such as the sarcro/endoplasmic reticulum Ca 2+ -ATPase (SERCA) protein; by inhibiting or downregulating expression of the Na + /Ca 2+ exchanger (NCX) protein; by expressing a calcium handling protein; by expressing a transverse (t)-tubule; and/or by expressing a transverse (t)-tubule biogenic protein. After the cell has been modified, it may be expanded to a substantially homogenous population of these cells or alternatively, differentiated to a more mature cell type. Compositions containing these cells and population of cells are also provided by this invention. The cells and compositions can be used to regenerate cardiac tissue, improve cardiac function, restore action potential of cardiac tissue; and treat or prevent cardiac malfunction. These methods can be achieved by administering an effective amount of a cell or population of cells or tissue of this invention to a host in need thereof. The cells and population of cells can be used diagnostically to screen drug or other therapeutic candidates.

What is claimed is: 
     
         1 . An isolated stem cell modified to provide functions of the sarcoplasmic reticulum (SR). 
     
     
         2 . An isolated stem cell of  claim 1 , wherein the cell expresses a calcium channel protein that is necessary to perform physiological functions. 
     
     
         3 . The isolated stem cell of  claim 2 , wherein the calcium channel protein is a ryanodine receptor (RyR) protein. 
     
     
         4 . The isolated stem cell of  claim 1 , further expressing a calcium pump protein that is necessary to perform physiological functions. 
     
     
         5 . The isolated stem cell of  claim 4 , wherein the calcium pump protein is a sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) protein. 
     
     
         6 . The isolated stem cell of  claim 1 , further comprising reduced expression of the Na + /Ca 2+  exchanger (NCX) protein. 
     
     
         7 . The isolated stem cell of  claim 1 , further expressing a calcium handling protein, wherein the protein is selected from the group consisting of calsequestrin, junctin, triadin and phospholamban. 
     
     
         8 . The isolated stem cell of  claim 1 , wherein the isolated stem cell further comprises the membrane structure transverse (t)-tubule. 
     
     
         9 . The isolated stem cell of  claim 1 , wherein the isolated stem cell expresses a cardiomyocyte marker selected from the group consisting of myosin heavy chain, myosin light chain, actinin, troponin and tropomyosin. 
     
     
         10 . The isolated stem cell of  claim 1 , wherein the stem cell is an embryonic stem cell or a pluripotent stem cell. 
     
     
         11 . A substantially homogeneous population of stem cells of  claim 1 . 
     
     
         12 . A substantially homogeneous population of stem cells expressing a calcium channel protein that is necessary to perform physiological functions. 
     
     
         13 . A composition comprising the stem cell of  claim 1  and a carrier. 
     
     
         14 . The composition of  claim 13 , wherein the carrier is a biocompatible scaffold. 
     
     
         15 . The composition of  claim 13 , wherein the carrier is a pharmaceutically acceptable carrier.