Method for promoting hematopoietic and mesenchymal cell proliferation and differentiation

Abstract

The present invention provides methods, improved cell culture medium and kits for promoting hematopoietic and mesenchymal stem and lineage-specific cell proliferation and differentiation by growth in the presence of angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (AII), AII analogues, AII fragments or analogues thereof or AII AT 2 type 2 receptor agonists, either alone or in combination with other growth factors and cytokines.

We claim:  
     
         1 . A method of accelerating the proliferation of mesenchymal stem cells comprising contacting the mesenchymal stem cells with an amount effective to accelerate proliferation of mesenchymal stem cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I  
       R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group.    
     
     
         2 . A method of accelerating the proliferation of hematopoietic lineage-specific cells comprising contacting the hematopoietic lineage-specific cells with an amount effective to accelerate proliferation of hematopoietic lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I  
       R 1 —R 2 —R 3 —R 4  —R 5 —R 6 —R 7- R 8    in which R 1  R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), He and Tyr, excluding sequences including R 4  as a terminal Tyr group.    
     
     
         3 . A method of accelerating the proliferation of mesenchymal lineage-specific cells comprising contacting the mesenchymal lineage-specific cells with an amount effective to accelerate proliferation of mesenchymal lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I  
       R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group.    
     
     
         4 . A method of accelerating the proliferation of hematopoietic lineage-specific cells comprising contacting the hematopoietic lineage-specific cells with an amount effective to accelerate proliferation of hematopoietic lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous ammo acids of groups R 1 -R 8  in the sequence of general formula I  
       R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group.    
     
     
         5 . A method of increasing the differentiation of hematopoietic stem or lineage-specific cells comprising contacting the hematopoietic stem or lineage-specific cells with an amount effective to increase differentiation of the hematopoietic stem or lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I  
       R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group.    
     
     
         6 . The method of  claim 5 , wherein the hematopoietic stem or lineage-specific cells are selected from the group consisting of macrophages and monocytes.  
     
     
         7 . The method of  claim 1 ,  2 ,  3 ,  4 ,  5 , or  6  wherein the active agent is selected from the group consisting of AII, AIII, AII(2-8), SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:31.  
     
     
         8 . The method of claims  1 ,  2 ,  3 ,  4 ,  5 , or  6  wherein the concentration of active agent is between about 0.1 ng/kg and about 1.0 mg/kg.  
     
     
         9 . An improved cell culture medium for growth of mesenchymal stem cells, wherein the improvement comprises addition to the cell culture medium of an amount effective to accelerate proliferation of mesenchymal stem cells of at least one active agent comprising a sequence, consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I  
       R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group.    
     
     
         10 . An improved cell culture medium for growth of hematopoietic lineage-specific cells, wherein the improvement comprises addition to the cell culture medium of an amount effective to accelerate proliferation of hematopoietic lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I  
       R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and. Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group.    
     
     
         11 . An improved cell culture medium for growth of mesenchymal lineage-specific cells, wherein the improvement comprises addition to the cell culture medium of an amount effective to accelerate proliferation of mesenchymal lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I  
       R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group.    
     
     
         12 . An improved cell culture medium for growth of hematopoietic lineage-specific cells, wherein the improvement comprises addition to the cell culture medium of an amount effective to accelerate proliferation of hematopoietic lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I  
       R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group.    
     
     
         13 . An improved cell culture medium for differentiation of hematopoietic stem or lineage-specific cells, wherein the improvement comprises addition to the cell culture medium an amount effective to increase differentiation of the hematopoietic stem or lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I  
       R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr,    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group.    
     
     
         14 . The method of  claim 13 , wherein the hematopoietic stem or lineage-specific cells are selected from the group consisting essentially of macrophages and monocytes.  
     
     
         15 . The improved cell culture medium of  claim 9 ,  10 ,  11 ,  12 ,  13 , or  14  wherein the active agent is selected from the group consisting of AII, AIII, AII(2-8), SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5,, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:31.  
     
     
         16 . The improved cell culture medium of  claim 9 ,  10 ,  11 ,  12 ,  13 , or  14  wherein the concentration of active agent is between about 0.1 ng/kg and about 1.0 mg/kg.  
     
     
         17 . A kit for the propagation of mesenchymal stem cells, comprising: 
 (a) an amount effective to accelerate proliferation of mesenchymal stem cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I    R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala, and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group; and      (b) instructions for using the amount effective of active agent as a cell culture medium supplement.    
     
     
         18 . The kit of  claim 17 , further comprising mesenchymal stem cell growth medium.  
     
     
         19 . A kit for the propagation of hematopoietic lineage-specific cells, comprising: 
 (a) an amount effective to accelerate proliferation of hematopoietic lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I    R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and      R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group; and    (b) instructions for using the amount effective of active agent as a cell culture medium supplement.    
     
     
         20 . The kit of  claim 19 , further comprising hematopoietic lineage-specific cell growth medium.  
     
     
         21 . A kit for the propagation of mesenchymal lineage-specific cells, comprising: 
 (a) an amount effective to accelerate proliferation of mesenchymal lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I    R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr,    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and      R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group; and    (b) instructions for using the amount effective of active agent as a cell culture medium supplement.    
     
     
         22 . The kit of  claim 21 , further comprising mesenchymal lineage-specific cell growth medium.  
     
     
         23 . A kit for the propagation of hematopoietic lineage-specific cells, comprising: 
 (a) an amount effective to accelerate proliferation of hematopoietic lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I    R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    f R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, le, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and      R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group; and    (b) instructions for using the amount effective of active agent as a cell culture medium supplement.    
     
     
         24 . The kit of  claim 23 , further comprising hematopoietic lineage-specific cell growth medium.  
     
     
         25 . A kit for the differentiation of hematopoietic stem or lineage-specific cells, comprising: 
 (a) an amount effective to accelerate differentiation of hematopoietic stem or lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 1 -R 8  in the sequence of general formula I    R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7- R 8    in which R 1  and R 2  together form a group of formula    X—R A —R B —,    wherein X is H or a one to three peptide group and a peptide bond between R A  and R B  is labile to aminopeptidase A cleavage;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and      R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences including R 4  as a terminal Tyr group.    (b) instructions for using the amount effective of active agent as a cell culture medium supplement.    
     
     
         26 . The kit of  claim 25 , wherein the hematopoietic stem or lineage-specific cells are selected from the group consisting of macrophages and monocytes.  
     
     
         27 . The kit of  claim 25  or  26 , further comprising hematopoietic lineage-specific cell growth medium.  
     
     
         28 . The kit of  claim 17 ,  18 ,  19 ,  20 ,  21 ,  22 ,  23 ,  24 ,  25 ,  26 , or  27  further comprising a sterile container.  
     
     
         29 . The kit of  claim 17 ,  18 ,  19 ,  20 ,  21 ,  22 ,  23 ,  24 ,  25 ,  26 , or  27  wherein the active agent is selected from the group consisting of AII, AIII, AII(2-8), SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:31.  
     
     
         30 . The kit of  claim 17 ,  18 ,  19 ,  20 ,  21 ,  22 ,  23 ,  24 ,  25 ,  26 , or  27  wherein the concentration of active agent is between about 0.1 ng/kg and about 1.0 mg/kg.  
     
     
         31 . A method of accelerating the proliferation of mesenchymal stem cells comprising contacting the mesenchymal stem cells with an amount effective to accelerate proliferation of mesenchymal stem cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II  
       R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr.    
     
     
         32 . A method of accelerating the proliferation of hematopoietic lineage-specific cells comprising contacting the hematopoietic lineage-specific cells with an amount effective to accelerate proliferation of hematopoietic lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II  
       R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr,    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), He and Tyr.    
     
     
         33 . A method of accelerating the proliferation of mesenchymal lineage-specific cells comprising contacting the mesenchymal lineage-specific cells with an amount effective to accelerate proliferation of mesenchymal lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II  
       R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr.    
     
     
         34 . A method of accelerating the proliferation of hematopoietic lineage-specific cells comprising contacting the hematopoietic lineage-specific cells with an amount effective to accelerate proliferation of hematopoietic lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II  
       R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr.    
     
     
         35 . A method of increasing the differentiation of hematopoietic stem or lineage-specific cells comprising contacting the hematopoietic stem or lineage-specific cells with an amount effective to increase differentiation of the hematopoietic stem or lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II  
       R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Try.    
     
     
         36 . The method of  claim 35 , wherein the hematopoietic stem or lineage-specific cells are selected from the group consisting of macrophages and monocytes.  
     
     
         37 . The method of  claim 31 ,  32 ,  33 ,  34 ,  35 , or  36  wherein the active agent is selected from the group consisting of SEQ ID NO:2, SEQ ID NO:17, and SEQ ID NO:18.  
     
     
         38 . The method of claims  31 ,  32 ,  33 ,  34 ,  35 , or  36  wherein the concentration of active agent is between about 0.1 ng/kg and about 1.0 mg/kg.  
     
     
         39 . An improved cell culture medium for growth of mesenchymal stem cells, wherein the improvement comprises addition to the cell culture medium of an amount effective to accelerate proliferation of mesenchymal stem cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II  
       R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr.    
     
     
         40 . An improved cell culture medium for growth of hematopoietic lineage-specific cells, wherein the improvement comprises addition to the cell culture medium of an amount effective to accelerate proliferation of hematopoietic lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II  
       R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr.    
     
     
         41 . An improved cell culture medium for grown of mesenchymal lineage-specific cells, wherein the improvement comprises addition to the cell culture medium of an amount effective to accelerate proliferation of mesenchymal lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II  
       R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr.    
     
     
         42 . An improved cell culture medium for growth of hematopoietic lineage-specific cells, wherein the improvement comprises addition to the cell culture medium of an amount effective to accelerate proliferation of hematopoietic lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II  
       R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr,    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr.    
     
     
         43 . An improved cell culture medium for differentiation of hematopoietic stem or lineage-specific cells, wherein the improvement comprises addition to the cell culture medium an amount effective to increase differentiation of the hematopoietic stem or lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II  
       R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr.    
     
     
         44 . The method of  claim 43 , wherein the hematopoietic stem or lineage-specific cells are selected from the group consisting of macrophages and monocytes.  
     
     
         45 . The improved cell culture medium of  claim 39 ,  40   41 ,  42 ,  43 , or  44  wherein the active agent is selected from the group consisting SEQ ID NO:2, SEQ ID NO:17, and SEQ ID NO:18.  
     
     
         46 . The improved cell culture medium of  claim 39 ,  40 ,  41 ,  42 ,  43 , or  44  wherein the concentration of active agent is between about 0.1 ng/kg and about 1.0 mg/kg.  
     
     
         47 . A kit for the propagation of mesenchymal stem cells, comprising: 
 (a) an amount effective to accelerate proliferation of mesenchymal stem cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II    R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr; and      (b) instructions for using the amount effective of active agent as a cell culture medium supplement.    
     
     
         48 . The kit of  claim 47 , further comprising mesenchymal stem cell growth medium.  
     
     
         49 . A kit for the propagation of hematopoietic lineage-specific cells, comprising: 
 (a) an amount effective to accelerate proliferation of hematopoietic lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous    amino acids of groups R 2 -R 8  in the sequence of general formula II    R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr; and      ;(b) instructions for using the amount effective of active agent as a cell culture medium supplement.    
     
     
         50 . The kit of  claim 49 , further comprising hematopoietic lineage-specific cell growth medium.  
     
     
         51 . A kit for the propagation of mesenchymal lineage-specific cells, comprising: 
 (a) an amount effective to accelerate proliferation of mesenchymal lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II    R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, and      (b) instructions for using the amount effective of active agent as a cell culture medium supplement.    
     
     
         52 . The kit of  claim 51 , further comprising mesenchymal lineage-specific cell growth medium.  
     
     
         53 . A kit for the propagation of hematopoietic lineage-specific cells, comprising: 
 (a) an amount effective to accelerate proliferation of hematopoietic lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II    R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr; and      (b) instructions for using the amount effective of active agent as a cell culture medium supplement.    
     
     
         54 . The kit of  claim 53 , further comprising hematopoietic lineage-specific cell growth medium.  
     
     
         55 . A kit for the differentiation of hematopoietic stem or lineage-specific cells, comprising: 
 (a) an amount effective to accelerate differentiation of hematopoietic stem or lineage-specific cells of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of groups R 2 -R 8  in the sequence of general formula II    R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8    in which R 2  is selected from the group consisting of H, Arg, Lys, Ala, Orn, Se r(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, norLeu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, norLeu, Val and Gly;    R 6  is His, Arg or 6-NH 2 -Phe;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr; and      (b) instructions for using the amount effective of active agent as a cell culture medium supplement.    
     
     
         56 . The kit of  claim 55 , wherein the hematopoietic stem or lineage-specific cells are selected from the group consisting of macrophages and monocytes.  
     
     
         57 . The kit of  claim 55  or  56 , further comprising hematopoietic lineage-specific cell growth medium.  
     
     
         58 . The kit of  claim 47 ,  48 ,  49 ,  50 ,  51 ,  52 ,  53 ,  54 ,  55 ,  56  or  57  further comprising a sterile container.  
     
     
         59 . The kit of  claim 47 ,  48 ,  49 ,  50 ,  51 ,  52 ,  53 ,  54 ,  55 ,  56 , or  57  wherein the active agent is selected from the group consisting of SEQ ID NO:2, SEQ ID NO:17, and SEQ ID NO:18.  
     
     
         60 . The kit of  claim 47 ,  48 ,  49 ,  50 ,  51 ,  52 ,  53 ,  54 ,  55 ,  56 , or  57  wherein the concentration of active agent is between about 0.1 ng/kg and about 1.0 mg/kg.