Agents for promoting tissue regeneration by recruiting bone marrow mesenchymal stem cells and/or pluripotent stem cells into blood

Abstract

It was revealed that the intravenous administration of HMGB-1 and S100A8 promoted the healing of skin ulcer by recruiting bone marrow-derived cells to the site of skin ulcer. Furthermore, when HMGB-1 was intravenously administered to cerebral infarction model mice after creation of cerebral infarction, bone marrow-derived cells expressing nerve cell markers were detected in their brain. A marked cerebral infarct-reducing effect was observed in mice intravenously administered with HMGB-1 as compared to the control. The post-cerebral infarction survival rate was increased in the intravenous HMGB-1 administration group. The involvement of bone marrow pluripotent stem cells in the process of bone fracture healing was assessed using mice, and the result demonstrated that bone marrow-derived cells distant from the damaged site migrated to the bone fracture site to repair the damaged tissue.

We claim: 
     
         1 . A tissue regeneration-promoting agent, comprising any one of:
 (a) an HMGB1 protein;   (b) a cell that secretes an HMGB1 protein;   (c) a vector into which a DNA encoding an HMGB1 protein is inserted;   (d) an HMGB2 protein;   (e) a cell that secretes an HMGB2 protein;   (f) a vector into which a DNA encoding an HMGB2 protein is inserted;   (g) an HMGB3 protein;   (h) a cell that secretes an HMGB3 protein;   (i) a vector into which a DNA encoding an HMGB3 protein is inserted;   (j) an S100A8 protein;   (k) a cell that secretes an S100A8 protein;   (l) a vector into which a DNA encoding an S100A8 protein is inserted;   (m) an S100A9 protein;   (n) a cell that secretes an S100A9 protein;   (o) a vector into which a DNA encoding an S100A9 protein is inserted;   (p) a cell or tissue extract; and   (q) a heparin-binding fraction of a cell or tissue extract;   wherein the agent is administered to a tissue other than a tissue in need of regeneration.   
     
     
         2 . The agent of  claim 1 , which is administered parenterally. 
     
     
         3 . The agent of  claim 2 , which is administered by injection. 
     
     
         4 . The agent of  claim 1 , which is administered intravascularly, intramuscularly, subcutaneously, intradermally, or intraperitoneally. 
     
     
         5 . The agent according to  claim 1 , wherein the cell or tissue extract is produced by a method comprising the step of immersing a cell or tissue in a solvent. 
     
     
         6 . The agent according to  claim 1 , wherein the heparin-binding fraction of a cell or tissue extract is produced by a method comprising the steps of:
 (a) immersing a cell or tissue in a solvent;   (b) contacting immobilized heparin with the extract prepared in step (a); and   (c) eluting a heparin-binding fraction from the immobilized heparin.   
     
     
         7 . The agent according to  claim 1  for use in promoting the regeneration of a nerve, bone, or skin tissue. 
     
     
         8 . A method for promoting tissue regeneration, which comprises the step of administering an effective amount of a composition to a tissue other than a tissue in need of regeneration, wherein the composition comprises any one of:
 (a) an HMGB1 protein;   (b) a cell that secretes an HMGB1 protein;   (c) a vector into which a DNA encoding an HMGB1 protein is inserted;   (d) an HMGB2 protein;   (e) a cell that secretes an HMGB2 protein;   (f) a vector into which a DNA encoding an HMGB2 protein is inserted;   (g) an HMGB3 protein;   (h) a cell that secretes an HMGB3 protein;   (i) a vector into which a DNA encoding an HMGB3 protein is inserted;   (j) an S100A8 protein;   (k) a cell that secretes an S100A8 protein;   (l) a vector into which a DNA encoding an S100A8 protein is inserted;   (m) an S100A9 protein;   (n) a cell that secretes an S100A9 protein;   (o) a vector into which a DNA encoding an S100A9 protein is inserted;   (p) a cell or tissue extract; and   (q) a heparin-binding fraction of a cell or tissue extract.   
     
     
         9 . The method of  claim 8 , wherein the administration is parenteral administration. 
     
     
         10 . The method of  claim 9 , wherein the administration is injection. 
     
     
         11 . The method of  claim 8 , wherein the administration is intravascular, intramuscular, subcutaneous, intradermal, or intraperitoneal administration. 
     
     
         12 . The method according to  claim 8 , which promotes the regeneration of a nerve, bone, or skin tissue.