Towards Personalized Cell-Replacement Therapies for Brain Repair

Alexandros A. Lavdas; Rebecca Matsas

Personalized Medicine. 2009;6(3):293-313.

Neutralization of Myelin-associated Inhibitors as an Adjuvant to cell Transplantation

Central nervous system white matter from higher vertebrates and cultured oligodendrocytes are nonpermissive substrates for neurite growth.^[5,6] Membrane proteins of 35 kd, and especially 250 kd (later renamed Nogo-A), were the first to be extracted from CNS myelin fractions that confer highly nonpermissive substrate properties.^[232] Applying neutralizing antisera and monoclonal anti-Nogo antibodies to these substrates has been demonstrated to significantly enhance neurite outgrowth on CNS myelin substrates and to enhance the ingrowth of neurites into adult rat optic nerve explants over many millimeters.^[232] The application of such antibodies in paraplegic patients is currently being studied in an ongoing clinical trial.^[233,241] Nogo-A contains multiple neurite outgrowth inhibitory domains that are exposed on the surface of the myelinating oligodendrocytes in its amino-terminal (amino-Nogo-A) and C-terminal (Nogo-66) regions. Nogo-66, as well as myelin-associated glycoprotein and myelin oligodendorcyte glycoprotein, exert their inhibitory effects by binding to the glycosylphosphatidylinositol-linked neuronal Nogo-66 receptor that transduces the inhibitory signal to the interior of the cell via transmembrane co-receptors LINGO-1 and p75 or TROY.^[234] Amino-Nogo-A and Nogo-66 receptor ligands activate the small GTPase, RhoA, and an antibody called cethrin that inhibits the Rho signaling pathway has already been used in a clinical trial with positive results,^[235,236] while the production of antibodies against the Nogo-66 receptor has also yielded positive results in animal studies.^[237] Combinatorial strategies using cell transplantation together with neutralization of growth-inhibitory molecules should further enhance the potential of either approach alone, and are therefore worthwhile testing in animal models.^[238]

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Abstract and Introduction
The Lesioned CNS
Stem Cells
Schwann Cells
Olfactory Ensheathing Cells
Neutralization of Myelin-associated Inhibitors as an Adjuvant to cell Transplantation
Conclusion
Future Perspective
References
Executive Summary

Executive Summary

The Lesioned CNS

The inability of the CNS to effectively regenerate lesions has been the driving force behind the efforts involved in cell-replacement therapies.

Stem Cells

The spectacular developments in stem-cell research in the last decade have created new hopes for cell-replacement therapies but have also produced new difficulties, both of a practical and an ethical nature.
The use of adult neural stem cells has provided encouraging results, but difficulties regarding their harvesting and propagation are serious drawbacks in their profile as candidates for autologous cell therapy. The derivation of neural stem cells from other somatic cell types holds some promise, but transdifferantiation into neural cell types has proven difficult. Umbilical cord stem cells and bone marrow stem cells have also raised hopes, although these are hampered by shortcomings related to differentiation and uncertainties regarding their mechanisms of action and incorporation in the lesioned sites.
Derivation of autologous pluripotent stem cells by nuclear reprogramming is considered the basis for any potential use of stem cells for personalized medicine.
The identification of a small number of master 'stemness' genes, the generation of induced pluripotent stem cells from adult somatic cells by introduction of three or four selected genes and their subsequent differentiation to the desired phenotypes, constitute a major advancement towards personalized cell-replacement therapies via autologous transplantation, and is expected to lead to clinically applicable solutions in the future.

Schwann Cells

Schwann cells represent attractive candidates for autologous cell-replacement therapies in the CNS as they promote axon regrowth, are easily obtainable and do not represent an immunological target in demyelinating diseases. Genetic or factor-related approaches are used to overcome shortcomings, mostly related to inefficient integration within the CNS tissue.

Olfactory Ensheathing Cells

Olfactory ensheathing cells are another group of glial cells with many promising features regarding their use in CNS cell-replacement therapy. They are easy to obtain and their affinity for the CNS environment is much higher than that of Schwann cells, while, on the other hand, their restorative capacity has not been as convincingly demonstrated.
Combinatorial approaches using Schwann cells, olfactory ensheathing cells and growth factors or factors limiting tissue damage are expected to pave the way for more efficient autologous glial-cell transplantation protocols. Alternatively, or in addition to, factors neutralizing the effects of myelin-associated inhibitors may further enhance the beneficial outcome of autologous cell-transplantation protocols.

Conclusion

The identification of a small number of master 'stemness' genes, the generation of induced pluripotent stem cells from adult somatic cells by introduction of selected genes and their subsequent differentiation to desired phenotypes constitute a significant advancement towards personalized cell-replacement therapies via autologous transplantation.
The transplantation of Schwann cells and olfactory ensheathing cells has been demonstrated to offer a degree of repair in various animal models of brain and spinal cord lesions, especially in combined protocols.

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