Repair of demyelinated lesions by transplantation of purified 0-2A progenitor cells

Abstract

The transplantation of well defined populations of precursor cells offers a means of repairing damaged tissue and of delivering therapeutic compounds to sites of injury or degeneration. For example, a functional immune system can be reconstituted by transplantation of purified haematopoietic stem cells, and transplanted skeletal myoblasts and keratinocytes can participate in the formation of normal tissue in host animals. Cell transplantation in the central nervous system (CNS) has been proposed as a means of correcting neuronal dysfunction in diseases associated with neuronal loss; it might also rectify glial cell dysfunction, with transplanted oligodendrocyte precursor cells eventually allowing repair of demyelinating damage in the CNS. Here we use co-operating growth factors to expand purified populations of oligodendrocyte type-2 astrocyte (O-2A) progenitor cells for several weeks in vitro. When injected into demyelinating lesions in spinal cords of adult rats, created in such a way as to preclude host-mediated remyelination, these expanded populations are capable of producing extensive remyelination. In addition, transplantation of O-2A progenitor cells genetically modified to express the bacterial beta-galactosidase gene gives rise to beta-galactosidase-positive oligodendrocytes which remyelinate demyelinated axons within the lesion. These results offer a viable strategy for the manipulation of neural precursor cells which is compatible with attempts to repair damaged CNS tissue by precursor transplantation.

Cell Therapy for Multiple Sclerosis

“…Although postmitotic oligodendrocytes have poor remyelinating capacity [123], their immediate progenitors exhibit greater mitotic, migratory, and regenerative properties in both genetic dysmyelinating and adult focal demyelinating models of disease [124][125][126][127]. Transplanted rodent OPCs myelinated nude axons and restored nerve conduction velocity to near normal values in the spinal cord of md rats [128], and canine OPCs repaired large brain areas in the sh pup [126].…”

Glial cells: Old cells with new twists

“…For many years, it was believed that they could also give rise to astrocytes type-2 glial cells (Raff et al, 1983). However, because upon transplantation these OPC cells differentiate only into myelinating oligodendrocytes (Groves et al, 1993), most scientists had assumed that the type-2 astrocyte generated in such studies was very likely an in vitro artifact induced on the precursor by the trophic factors present in the media (Franklin et al, 1995;Sawamura et al, 1995). What is more important regarding these precursors is that the cells formerly known as O-2A will not differentiate into neurons under any culture conditions tested; in other words, OPC is a true glial precursor.…”

Stem cell therapy and gene transfer for regeneration

“…17,18 Genetically engineered NSCs have been shown to differentiate selectively into oligodendrocytes, which, after in vitro expansion, were used to remyelinate the vast majority of axons after transplantation in a demyelinated area. 39 Furthermore, recombinant adenoviral vectors can successfully transfect human neural progenitor cells with exogenous genes allowing options of ex vivo gene therapy. 40 In fact, transplantation of NSCs genetically modified to secrete nerve growth factor (NGF) was able to ameliorate the death of striatal projection neurons caused by transient focal ischemia in the adult rat.…”