Conditioning protocols and use of same for tissue regeneration

Abstract

A method of conditioning a subject in need of transplantation of progenitor cells in suspension of a tissue of interest is disclosed. The method comprising: (a) administering to a subject a therapeutically effective amount of an agent capable of inducing damage to the tissue of interest, wherein the damage results in proliferation of resident stem cells in the tissue; and subsequently (b) subjecting the subject to an agent which ablates the resident stem cells in the tissue. A method of transplanting progenitor cells in suspension of a tissue of interest to a subject in need thereof is also disclosed.

What is claimed is: 
     
         1 . A method of transplanting ex vivo differentiated progenitor cells in suspension of a tissue of interest to a subject in need thereof, the method comprising:
 (a) conditioning the subject by:
 (i) administering to the subject a therapeutically effective amount of an agent capable of inducing damage to the tissue of interest, wherein said damage results in proliferation of resident stem cells in the tissue, and wherein when the tissue of interest is a pulmonary tissue said agent capable of inducing damage to the tissue is not naphthalene; and subsequently 
 (ii) subjecting the subject to an agent which ablates said resident stem cells in said tissue, thereby conditioning the subject; and 
   (b) transplanting the ex vivo differentiated progenitor cells in suspension to said subject.   
     
     
         2 . The method of  claim 1 , wherein said ex vivo differentiated progenitor cells comprise human progenitor cells. 
     
     
         3 . The method of  claim 1 , wherein said ex vivo differentiated progenitor cells are from adult stem cells. 
     
     
         4 . The method of  claim 1 , wherein said ex vivo differentiated progenitor cells are from pluripotent stem cells. 
     
     
         5 . The method of  claim 4 , wherein said pluripotent stem cells comprise embryonic stem cells or induced pluripotent stem cells (iPS). 
     
     
         6 . The method of  claim 1 , wherein said ex vivo differentiated progenitor cells are capable of regenerating a structural/functional tissue. 
     
     
         7 . The method of  claim 1 , wherein said subject has a disease selected from the group consisting of a pulmonary disease, a malignant disease, a disease of the central nervous system, a gastrointestinal disease, a cardiovascular disease, a hepatic disease, a nephric disease, a pancreatic disease, an infectious disease, an inflammatory disease, an immunodeficiency and an autoimmune disease. 
     
     
         8 . The method of  claim 1 , wherein said ex vivo differentiated progenitor cells are selected from the group consisting of pulmonary progenitor cells, cardiac progenitor cells, hepatic progenitor cells, pancreatic progenitor cells, brain progenitor cells, nephric progenitor cells, ovarian progenitor cells and spleen progenitor cells. 
     
     
         9 . The method of  claim 1 , wherein said tissue of interest is selected from the group consisting of a pulmonary tissue, a cardiac tissue, a hepatic tissue, a pancreatic tissue, a brain tissue, a nephric tissue, an ovarian tissue and a spleen tissue. 
     
     
         10 . The method of  claim 1 , wherein said agent capable of inducing damage to said tissue is selected from the group consisting of a chemical, an antibiotic, a therapeutic drug, a toxin, a surgical intervention and a herbal remedy. 
     
     
         11 . The method of  claim 1 , wherein said agent capable of inducing damage to said tissue is selected from the group consisting of an agent causing pulmonary cell toxicity, an agent causing renal cell toxicity, an agent causing hepatic cell toxicity, an agent causing cardiac cell toxicity, an agent causing pancreatic cell toxicity, an agent causing brain cell toxicity, an agent causing spleen cell toxicity and an agent causing ovarian cell toxicity. 
     
     
         12 . The method of  claim 11 , wherein:
 said agent causing pulmonary cell toxicity is selected from the group consisting of a chemotherapeutic agent, an immunosuppressive agent, an amiodarone, a beta blockers, an ACE inhibitor, a nitrofurantoin, a procainamide, a quinidine, a tocainide, and a minoxidil;   said agent causing renal cell toxicity is selected from the group consisting of an aminoglycoside antibiotic, a calcineurin inhibitor, an acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), an antidepressant, an antihistamine, an anti-microbial agent, an anti-retroviral agent, a benzodiazepine, a cardiovascular agent, a chemotherapeutic agent, a herbal remedy and partial nephrotectomy;   said agent causing hepatic cell toxicity is selected from the group consisting of an acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), a glucocorticoid, an isoniazid, a hydrazine derivative drug, an industrial toxin, a herbal remedy and partial hepatectomy;   said agent causing cardiac cell toxicity is selected from the group consisting of a chemotherapeutic agent, a cytostatic agent, an antidepressant drug, an immunomodulating drug, an anesthetic, a calcium channel blocking agent, a nonsteroidal anti-inflammatory drug (NSAID), a beta-adrenoceptor antagonist and an antiarrhythmic;   said agent causing pancreatic cell toxicity is selected from the group consisting of an ACE inhibitor, an azathioprine, an estrogen, a furosemide, a methyldopa, a mesalazine, a pentamidine, a procainamide, a propofol, a statin, a streptozotocin, a sulfonamide, a thiazide diuretic, a valproate and a partial pancreatectomy;   said agent causing brain cell toxicity is selected from the group consisting of an antihistamine, a bladder relaxant, a muscle relaxant, an antidepressant and a chemotherapeutic agent;   said agent causing ovarian cell toxicity is selected from the group consisting of a chemotherapeutic agent and an immunosuppressive agent.   
     
     
         13 . The method of  claim 1 , wherein said agent capable of inducing damage to said tissue is an Alkylating agent. 
     
     
         14 . The method of  claim 13 , wherein said Alkylating agent is selected from the group consisting of a cyclophosphamide and a busulfan. 
     
     
         15 . The method of  claim 1 , wherein said agent which ablates said resident stem cells comprises a partial body irradiation, a total body irradiation (TBI), or an Alkylating agent. 
     
     
         16 . The method of  claim 15 , wherein said partial body irradiation or TBI comprises a single or fractionated irradiation dose within the range of 1-7.5 Gy. 
     
     
         17 . The method of  claim 15 , wherein said Alkylating agent is selected from the group consisting of a cyclophosphamide and a busulfan. 
     
     
         18 . The method of  claim 1 , wherein said agent capable of inducing damage to said tissue is administered to the subject 1-3 days prior to said agent which ablates said resident stem cells. 
     
     
         19 . The method of  claim 1 , wherein said subject is a human being. 
     
     
         20 . The method of  claim 1 , wherein said transplanting is effected by a route selected from the group consisting of intratracheal, intrabronchial, intraalveolar, intravenous, intraperitoneal, intranasal, subcutaneous, intramedullary, intrathecal, intraventricular, intracardiac, intramuscular, intrasrosal, intramucosal, transmucosal, transnasal, rectal and intestinal. 
     
     
         21 . The method of  claim 1 , wherein said transplanting is effected by an intravenous route. 
     
     
         22 . The method of  claim 1 , further comprising treating the subject with an immunosuppressive regimen.