Side population cells in cardiac repair

Abstract

It has been discovered that side-population cells induce cardiac tissue repair of infarcted myocardium. Provided herein are methods directed to treatment of cardiac injury using side-population cells.

1 . A method for restoring cardiac function in a subject in need thereof comprising:
 introducing an effective amount of a composition comprising side-population (SP) cells into a heart region comprising a myocardial infarction,   wherein said SP cells
 (i) are isolated by gating on Hoechst 33342 dye; 
 (ii) are transformed with a nucleic acid sequence encoding a Cyclin A2 protein; and 
 (iii) exogenously express a Cyclin A2 protein; 
   wherein restoring said cardiac function comprises improving ejection fraction.   
     
     
         2 . The method of  claim 1  wherein the composition further comprises a pharmaceutically acceptable carrier. 
     
     
         3 . The method of  claim 1  wherein the subject is diagnosed with, or at risk for, myocardial infarction, chronic coronary ischemia, arteriosclerosis, congestive heart failure, dilated cardiomyopathy, restenosis, coronary artery disease, heart failure, arrhythmia, angina, atherosclerosis, hypertension, or myocardial hypertrophy. 
     
     
         4 . The method of  claim 3  wherein the subject is diagnosed with myocardial infarction. 
     
     
         5 . The method of  claim 3  wherein the subject has or is at risk for heart failure. 
     
     
         6 . The method of  claim 1  wherein introducing the composition comprises implanting the composition into cardiac tissue of the subject. 
     
     
         7 . The method of  claim 6  wherein the cardiac tissue is selected from the group consisting of myocardium, endocardium, epicardium, connective tissue in the heart, and nervous tissue in the heart. 
     
     
         8 . The method of  claim 1  wherein the subject is an animal. 
     
     
         9 . The method of  claim 8  wherein the subject is a mammal. 
     
     
         10 . The method of  claim 9  wherein the subject is a human. 
     
     
         11 . The method of  claim 1  wherein the amount of introduced composition comprising side-population cells is sufficient to increase cardiomyocyte formation, increase cardiomyocyte proliferation, increase cardiomyocyte cell cycle activation, increase mitotic index of cardiomyocytes, increase myofilament density, increase borderzone wall thickness, increase volumetric ejection fraction, or a combination thereof. 
     
     
         12 . The method of  claim 1  wherein the amount of introduced composition comprises about 1×10 8  to about 1×10 2  side population cells. 
     
     
         13 . The method of  claim 12  wherein the amount of introduced composition comprises about 1×10 6  to about 1×10 5  side population cells. 
     
     
         14 . The method of  claim 1 , wherein a nucleic acid sequence encoding cyclin A2 is introduced into the side population cells via a viral vector. 
     
     
         15 . The method of  claim 14 , wherein the viral vector is a lentiviral vector, a retroviral vector, an adenoviral vector, or an adeno-associated viral vector. 
     
     
         16 . The method of  claim 14 , wherein the viral vector is an adenoviral vector or an adeno-associated viral vector. 
     
     
         17 . The method of  claim 14 , further comprising transducing the side-population cell with the viral vector. 
     
     
         18 . The method of  claim 17 , wherein the side-population cell is transduced with the viral vector before the composition is introduced into the heart of the subject. 
     
     
         19 . The method of  claim 1 , wherein the side-population cells are derived from the subject. 
     
     
         20 . The method of  claim 1 , wherein the side-population cells have been isolated by gating on Hoechst 33342 dye via fluorescent activated cell sorting. 
     
     
         21 . The method of  claim 14 , wherein the viral vector is a lentiviral vector. 
     
     
         22 . The method of  claim 11 , wherein the amount of introduced composition comprising side-population cells is sufficient to increase cardiomyocyte formation, increase mitotic index of cardiomyocytes, or a combination thereof. 
     
     
         23 . The method of  claim 11 , wherein the amount of introduced composition comprising side-population cells is sufficient to increase volumetric ejection fraction. 
     
     
         24 . The method of  claim 1 , further comprising introducing into the heart of the subject an amount of a second composition comprising a nucleic acid sequence encoding a cyclin protein. 
     
     
         25 . A method for restoring cardiac function in a subject in need thereof comprising:
 introducing into a peri-infarct zone of a heart an effective amount of a composition comprising side-population (SP) cells,   wherein said SP cells
 (i) are isolated from bone marrow by gating on Hoechst 33342 dye; 
 (ii) are transformed with a nucleic acid sequence construct comprising an adenoviral vector encoding a cyclin A2 protein operably linked to a heart-specific promoter; and 
 (iii) exogenously express the Cyclin A2 protein; 
   wherein said heart comprises a myocardial infarction; and   wherein restoring cardiac function comprises increased heart ejection fraction.   
     
     
         26 . The method of  claim 1 , wherein the side-population cells are isolated from bone marrow. 
     
     
         27 . The method of  claim 1 , wherein the side-population cells are isolated from heart tissue.