Lineage Restricted Glial Precursors from the Central Nervous System

Abstract

A glial precursor cell population from mammalian central nervous system has been isolated. These A2B5 + E-NCAM − glial-restricted precursor (GRP) cells are capable of differentiating into oligodendrocytes, A2B5 + process-bearing astrocytes, and A2B5 − fibroblast-like astrocytes, but not into neurons. GRP cells can be maintained by regeneration in culture. GRP cells differ from oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells in growth factor requirements, morphology, and progeny. Methods of use of GRP cells are also disclosed.

1 . An isolated population of mammalian CNS glial restricted precursor cells that is capable of generating oligodendrocytes and at least two distinct populations of astrocytes, wherein said glial restricted precursor cells express cell surface antigens recognized by the A2B5 monoclonal antibody, but do not express embryonic neural cell adhesion molecule. 
     
     
         2 . The population of  claim 1  wherein said glial restricted precursor cells are capable of differentiating into oligodendrocytes, A2B5-positive process-bearing astrocytes, and A2B5-negative astrocytes with fibroblast-like morphology. 
     
     
         3 . A method for treating a neurological or neurodegenerative disease comprising administering to a mammal in need of such treatment an effective amount of the glial restricted precursor cells of  claim 1  or derivatives thereof or mixtures thereof. 
     
     
         4 . A method for treating neurodegenerative symptoms in a mammal comprising the steps of:
 (a) providing the glial restricted precursor cells of  claim 1 ;   (b) genetically transforming said glial restricted precursor cells with a gene encoding a growth factor, neurotransmitter, neurotransmitter synthesizing enzyme, neuropeptide, neuropeptide synthesizing enzyme, or substance that provides protection against free-radical mediated damage thereby resulting in a transformed population of glial restricted precursor cells that express said growth factor, neurotransmitter, neurotransmitter synthesizing enzyme, neuropeptide, neuropeptide synthesizing enzyme, or substance that provides protection against free-radical mediated damage; and   (c) administering an effective amount of said transformed population of glial restricted precursor cells to said mammal.   
     
     
         5 . A method for promoting wound healing at a lesion site in the central nervous system comprising the steps of:
 (a) providing a composition comprising glial restricted precursor cells of  claim 1  or derivatives thereof or mixtures thereof;   (b) administering an effective amount of said composition into and adjacent to said lesion site within two weeks following traumatic injury thereto.   
     
     
         6 . A method for promoting neuronal survival or axonal regeneration or both in the central nervous system comprising administering an effective amount of the glial restricted precursor cells or derivatives thereof or mixtures thereof of  claim 1  to the CNS of the mammal into regions of neuronal injury or regions in which axonal regeneration is required. 
     
     
         7 . A method for treating neurodegenerative symptoms in a mammal comprising administering an effective amount of the restricted precursor cells or derivatives thereof or mixtures thereof of  claim 1  to the CNS of the mammal. 
     
     
         8 . A method for treating neurodegenerative symptoms in a mammal comprising placing the glial restricted precursor cells or derivatives thereof or mixtures thereof of  claim 1  in an encapsulation device to result in encapsulated cells and administering an effective amount of the encapsulated cells to the CNS of the mammal. 
     
     
         9 . A method for treating neurodegenerative symptoms in a mammal comprising placing the glial restricted precursor cells or derivatives thereof or mixtures thereof of  claim 1  on or in a scaffold to result in scaffold-associated cells and administering an effective amount of the scaffold-associated cells to the CNS of the mammal. 
     
     
         10 . A method for promoting axonal growth along defined scaffolds comprising implanting a scaffold such that a bridge is formed between a region where a desired population of neurons exists and a region to which neuronal growth is desired and placing an effective amount of the glial restricted precursor cells or derivatives thereof or mixtures thereof of  claim 1  on or in the scaffold. 
     
     
         11 . A method for screening compounds for neurological activity comprising the steps of:
 (a) providing a population of glial restricted precursor cells or derivatives thereof or mixtures thereof of  claim 1  cultured in vitro;   (b) exposing said cells or derivatives thereof or mixtures thereof to a selected compound at varying dosages; and   (c) monitoring the reaction of said cells or derivatives thereof or mixtures thereof to said selected compound for selected time periods.   
     
     
         12 . A method for screening for a compound that inhibits binding to a selected receptor on a glial restricted precursor cell, said method comprising contacting glial restricted precursors of  claim 1  with a compound and determining the ability of the compound to block a response elicited by binding of an agonist to the selected receptor on the glial restricted precursor cells. 
     
     
         13 . A method for screening for compounds which activate a selected receptor on a glial restricted precursor cell, said method comprising contacting glial restricted precursors of  claim 1  with a compound and measuring a physiological alteration in said cells associated with activation of said receptor. 
     
     
         14 . A method for continuously propagating glial restricted precursor cells comprising culturing glial restricted precursor cells of  claim 1  in vitro in the presence of minimal essential salts and effective amounts of platelet derived growth factor and fibroblast growth factor.