Survival and differentiation of oligodendrocytes from neural tissue transplanted into new-born mouse brain

364

244

Many diseases of the central nervous system (CNS), particularly those of genetic, metabolic, or infectious͞ inflammatory etiology, are characterized by ''global'' neural degeneration or dysfunction. Therapy might require widespread neural cell replacement, a challenge not regarded conventionally as amenable to neural transplantation. Mouse mutants characterized by CNS-wide white matter disease provide ideal models for testing the hypothesis that neural stem cell transplantation might compensate for defective neural cell types in neuropathologies requiring cell replacement throughout the brain. The oligodendrocytes of the dysmyelinated shiverer (shi) mouse are ''globally'' dysfunctional because they lack myelin basic protein (MBP) essential for effective myelination. Therapy, therefore, requires widespread replacement with MBP-expressing oligodendrocytes. Clonal neural stem cells transplanted at birthusing a simple intracerebroventricular implantation technique-resulted in widespread engraftment throughout the shi brain with repletion of MBP. Accordingly, of the many donor cells that differentiated into oligodendroglia-there appeared to be a shift in the fate of these multipotent cells toward an oligodendroglial fate-a subgroup myelinated up to 52% (mean ‫؍‬ Ϸ40%) of host neuronal processes with better compacted myelin of a thickness and periodicity more closely approximating normal. A number of recipient animals evinced decrement in their symptomatic tremor. Therefore, ''global'' neural cell replacement seems feasible for some CNS pathologies if cells with stem-like features are used.

Section: Resultsmentioning

confidence: 98%

“Global” cell replacement is feasible via neural stem cell transplantation: Evidence from the dysmyelinated shiverer mouse brain

Yandava

Billinghurst

Snyder

1999

364

244

“…Because homozygous shiverer mice do not exhibit MBP immunoreactivity (Fig. 6E) (27,28), all MBP immunoreactivity could be attributed to the transplanted ES cell-derived oligodendrocytes. In mice that received oligosphere transplantation, but not in mice that received sham transplantation, MBP immunoreactivity was evident in a radial longitudinal gradient paralleling the white matter tract.…”

Section: Resultsmentioning

confidence: 99%

“…As an injury model, localized chemical demyelination was induced in the dorsal column white matter of rats while sparing passing axons (23)(24)(25)(26). Myelin-deficient shiverer (shi/shi) mutant mice, lacking the gene to produce myelin basic protein (MBP) (27)(28)(29)(30)(31), were used as a noninjury model where transplanted oligodendrocytes and newly produced myelin could be identified by immunoreactivity for MBP. retinoic acid protocol (15,33).…”

mentioning

confidence: 99%

“…Homozygous shiverer (shi/shi) mice are devoid of MBP because they lack the functional gene. Thus, the presence of MBP ϩ myelin in these animals following transplantation provides a useful marker for confident identification of transplanted oligodendrocytes (27,28). Anti-neuron-specific nuclear antigen (Chemicon; identifies a neuron-specific nuclear protein in postmitotic cells), anti-neuron-specific enolase (Chemicon; reacts with neuronspecific enolase), and anti-␤-tubulin III (Sigma; reacts with neuron specific tubulin) were used to identify neurons.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation

Liu

Stewart

et al. 2000

507

318

Demyelination contributes to the loss of function consequent to central nervous system (CNS) injury. Enhanced remyelination through transplantation of myelin-producing cells may offer a pragmatic approach to restoring meaningful neurological function. An unlimited source of cells suitable for such transplantation therapy can be derived from embryonic stem (ES) cells, which are both pluripotent and genetically flexible. In this paper we show that oligodendrocyte cultures can be reliably produced from retinoic acid-induced ES cells and that these oligodendrocytes can myelinate axons in vitro. Methods were further developed for generating highly enriched cultures of oligodendrocytes through an additional culturing step, producing an intermediate ''oligosphere'' stage. To test whether ES cells can survive, migrate, and differentiate into mature myelin-producing cells in areas of demyelination in the adult CNS, ES cells were transplanted into the dorsal columns of adult rat spinal cord 3 days after chemical demyelination. In the demyelination site, large numbers of ES cells survived and differentiated primarily into mature oligodendrocytes that were capable of myelinating axons. Furthermore, when oligosphere cells were transplanted into the spinal cords of myelindeficient shiverer (shi/shi) mutant mice, the ES cell-derived oligodendrocytes migrated into the host tissue, produced myelin and myelinated host axons. These studies demonstrate the ability of ES cell-derived oligodendrocytes to myelinate axons in culture and to replace lost myelin in the injured adult CNS. Transplantation of ES cells may be a practical approach to treatment of primary and secondary demyelinating diseases in the adult CNS. R ecovery in central nervous system (CNS) disorders is hindered by the limited ability of the vertebrate CNS to regenerate lost cells, replace damaged myelin, and re-establish functional neural connections. In many CNS disorders, including multiple sclerosis, stroke, spinal cord injury, and other trauma, demyelination of intact axons (1-4) is an important factor contributing to loss of function. Previous studies suggest that substantial recovery of function might be achieved through remyelination of otherwise intact axons (5). As a therapeutic modality, functional recovery through remyelination may prove to be a pragmatic approach to regeneration.Ethical considerations and a lack of a reliable source for undifferentiated pluripotent cells have limited the application of neural transplantation studies in humans. Embryonic stem cells (ES cells) provide a partial solution to these problems because they are genetically normal, pluripotent, capable of indefinite replication (6), and have been derived from several vertebrate species including mice (7,8) The purpose of the present studies was threefold: (i) to develop methods for producing enriched cultures of ES cell-derived oligodendrocytes, (ii) to determine whether these cells could myelinate axons in vitro, and (iii) to determine whether ES cells would survive transplantati...

“…A number of therapeutic strategies to promote remyelination have been tested in experimental animals. Transplantation of OLs (5) or their progenitors (6) into demyelinated tissue produces new myelin. Transplanted OL progenitors also can remyelinate demyelinated lesions in the adult CNS (7) and migrate toward an area of damage when placed in close proximity to the lesion (8).…”

mentioning

confidence: 99%

Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis

Warrington

Asakura

Bieber

et al. 2000

237

204

Promoting remyelination, a major goal of an effective treatment for demyelinating diseases, has the potential to protect vulnerable axons, increase conduction velocity, and improve neurologic deficits. Strategies to promote remyelination have focused on transplanting oligodendrocytes (OLs) or recruiting endogenous myelinating cells with trophic factors. Ig-based therapies, routinely used to treat a variety of neurological and autoimmune diseases, underlie our approach to enhance remyelination. We isolated two human mAbs directed against OL surface antigens that promoted significant remyelination in a virusmediated model of multiple sclerosis. Four additional OL-binding human mAbs did not promote remyelination. Both human mAbs were as effective as human i.v. Ig, a treatment shown to have efficacy in multiple sclerosis, and bound to the surface of human OLs suggesting a direct effect of the mAbs on the cells responsible for myelination. Alternatively, targeting human mAbs to areas of central nervous system (CNS) pathology may facilitate the opsonization of myelin debris, allowing repair to proceed. Human mAbs were isolated from the sera of individuals with a form of monoclonal gammopathy. These individuals carry a high level of monoclonal protein in their blood without detriment, lending support to the belief that administration of these mAbs as a therapy would be safe. Our results are (i) consistent with the hypothesis that CNS-reactive mAbs, part of the normal Ig repertoire in humans, may help repair and protect the CNS from pathogenic immune injury, and (ii) further challenge the premise that Abs that bind OLs are necessarily pathogenic. E nhancement of remyelination and protection from axonal injury are important therapeutic goals in the treatment of inflammatory demyelinating central nervous system (CNS) disorders such as multiple sclerosis (MS). Remyelination in MS plaques can occur, but is limited (1, 2) even though oligodendrocyte (OL) progenitors are present in the adult (3, 4). A number of therapeutic strategies to promote remyelination have been tested in experimental animals. Transplantation of OLs (5) or their progenitors (6) into demyelinated tissue produces new myelin. Transplanted OL progenitors also can remyelinate demyelinated lesions in the adult CNS (7) and migrate toward an area of damage when placed in close proximity to the lesion (8). Unresolved issues remain concerning the survival of transplanted OL progenitors in the intact adult CNS and their ability to target to areas of myelin pathology (9). However, if CNS lesions are surgically approachable and axons are still intact, transplantation of glial cells may be a viable therapy for improving functional performance (10).The in vitro administration of growth or trophic factors induces the expansion of OL progenitors (11, 12) or promotes mature OLs to dedifferentiate and subsequently reinitiate a program of myelination (13,14). The in vivo administration of trophic factors via genetically engineered fibroblasts to the injured CNS promotes ax...