Compositions for proliferation of cells and related methods

Abstract

We have discovered that p63 inhibition results in increased cellular proliferation. We have also performed a screen for agents capable of increasing cellular proliferation, (e.g., of stem cells such as skin-derived precursors (SKPs)). The invention therefore invention provides compositions, methods, and kits for increasing proliferation of cells, using compounds that decrease p63 expression or activity or using the compounds described herein. The invention also features methods of using these compounds for increasing hair growth, improving skin health, or promoting skin repair in a subject.

What is claimed is: 
     
         1 . A method of increasing proliferation of a cell, said method comprising contacting said cell with a sufficient amount of one or more of:
 (a) a compound that decreases p63 expression or activity, or   (b) a compound selected from the group consisting of acyclovir, alprostadil, aristolochic acid, carbadox, chlorpyrifos, cyclocreatine, 7,4′-dimethoxyisoflavone, dorzolamide, S(−)eticlopride, evoxine, guaifenesin, hydroxyprogesterone, kaempferol, linamarin, mexicanolide, MG 624, pramoxine, tannic acid, targinine, alpha-methyllycacontine, mecamylamine hexamethonium, alsterpaullone, and yohimbic acid, or an analog thereof, under conditions that support cell proliferation.   
     
     
         2 . The method of  claim 1 , wherein said cell is from a tumor cell line, is a stem cell, or is a skin-derived precursor (SKP). 
     
     
         3 . The method of  claim 1 , wherein said cell is contacted with (a) alprostadil and kaempferol or (b) alprostadil and pramoxine. 
     
     
         4 . The method of  claim 1 , wherein said cell is being cultured in vitro. 
     
     
         5 . The method of  claim 4 , wherein said cell culture further comprises an additional growth factor or said cell culture further comprises FGF2 or EGF. 
     
     
         6 . A composition comprising:
 (a) an isolated stem cell; and   (b) one or more compounds that decrease p63 expression or activity and/or one or more compounds selected from the group consisting of acyclovir, alprostadil, aristolochic acid, carbadox, chlorpyrifos, cyclocreatine, 7,4′-dimethoxyisoflavone, dorzolamide, S(−) eticlopride, evoxine, guaifenesin, hydroxyprogesterone, kaempferol, linamarin, mexicanolide, MG 624, pramoxine, tannic acid, targinine, alpha-methyllycacontine, mecamylamine hexamethonium, alsterpaullone, and yohimbic acid, or an analog thereof, wherein said compound is present in an amount sufficient to promote proliferation of said stem cell.   
     
     
         7 . The composition of  claim 6 , wherein said stem cell is a SKP. 
     
     
         8 . The composition of  claim 6  further comprising a growth factor, FGF2, or EGF. 
     
     
         9 . The composition of  claim 6 , wherein said compounds are (a) alprostadil and kaempferol or (b) alprostadil and pramoxine. 
     
     
         10 . A composition comprising:
 (a) one or more compounds that decrease p63 expression or activity and/or one or more compounds selected from the group consisting of acyclovir, alprostadil, aristolochic acid, carbadox, chlorpyrifos, cyclocreatine, 7,4′-dimethoxyisoflavone, dorzolamide, S(−)eticlopride, evoxine, guaifenesin, hydroxyprogesterone, kaempferol, linamarin, mexicanolide, MG 624, pramoxine, tannic acid, targinine, alpha-methyllycacontine, mecamylamine hexamethonium, alsterpaullone, and yohimbic acid, or an analog thereof; and   (b) a carrier suitable for topical administration.   
     
     
         11 . The composition of  claim 10 , wherein said carrier is a lotion. 
     
     
         12 . The composition of  claim 10 , wherein said compounds are (a) alprostadil and kaempferol or (b) alprostadil and pramoxine. 
     
     
         13 . A method of increasing SKP proliferation in a subject, promoting hair growth, repairing skin, or improving skin health in a subject, said method comprising administering a sufficient amount of:
 (a) one or more compounds that inhibit p63 expression or activity; and/or   (b) one or more compounds selected from the group consisting of acyclovir, alprostadil, aristolochic acid, carbadox, chlorpyrifos, cyclocreatine, 7,4′-dimethoxyisoflavone, dorzolamide, S(−)eticlopride, evoxine, guaifenesin, hydroxyprogesterone, kaempferol, linamarin, mexicanolide, MG 624, pramoxine, tannic acid, targinine, alpha-methyllycacontine, mecamylamine hexamethonium, alsterpaullone, and yohimbic acid, or an analog thereof.   
     
     
         14 . The method of  claim 13 , wherein said subject has a wound, and said compound is administered in an amount sufficient to improve healing of said wound. 
     
     
         15 . The method of  claim 13 , wherein said compounds are (a) alprostadil and kaempferol or (b) alprostadil and pramoxine. 
     
     
         16 . The method of  claim 13 , wherein said compound is administered topically or systemically. 
     
     
         17 . The method of  claim 13 , wherein said administration of said one or more compounds reduces wrinkles in the skin of said subject. 
     
     
         18 . The method of  claim 13 , wherein said subject is a human. 
     
     
         19 . A method of identifying a compound capable of altering cell proliferation, said method comprising:
 (a) contacting a SKP with a candidate compound; and   (b) determining the proliferation rate of said SKP, wherein an alteration in the proliferation rate of said SKP in the presence of said compound as compared to in the absence of said compound, indicates that said compound alters the rate of cell proliferation.   
     
     
         20 . The method of  claim 19 , wherein said SKP cell is a human, mouse, or rat cell.