Cell Therapy for Multiple Sclerosis
Tamir Ben-Hur
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) Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah - Hebrew University Hospital
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Jerusalem 91120, Israel
The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.
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Although current therapy in multiple sclerosis (MS) is
directed at the underlying autoimmune pathogenic process,
cell therapy has been advocated as a means of regenerative
medicine. In this review, the complexity, advantages, and
difficulties in cell therapy will be discussed.
Is Cell Therapy a Valid Option for MS?
Any discussion of cell therapy for MS needs to first take a
look at the endogenous processes of brain repair and their
failure to build a rationale for the feasibility and prospects
of treatment by cell transplantation.
Glial Progenitor Cells in the Adult Central Nervous System
The identification of neural precursor cells and
neurogenesis in the adult central nervous system (CNS) [13],
including that of humans [46], and the identification of
persistent neural stem cells (NSCs) as the parental cells
from which new neurons are derived [714], has
revolutionized our concepts of the adult brain as structurally
immutable. There are several niches in the adult brain in
which NSCs persist throughout life and can respond to
injurious processes [1518]. New neurons are continuously
generated in the anterior subventricular zone (SVZ) of adult
rodents, from which they migrate via the rostral migratory
stream to the olfactory bulb [1923], and in the subgranular
zone of the hippocampal dentate gyrus of both adult rodents
[2427] and humans [6, 28]. The subependymal cell layer
of the ventricles [29] and spinal cord [30] contains stem
cells that give rise to both neurons and glia. Multi-potential
precursors are abundant in many regions of the adult brain
parenchyma [3134]. In particular, oligodendrocyte
progenitor cells (OPCs) were isolated from various regions of
the adult rodent CNS [3537], and were identified also in
the adult human brain [3842] and spinal cord [43]. OPCs
are identified by expression of chondroitin-sulfate
proteoglycan NG2+ and of platelet-derived growth factor
receptor- are highly abundant in the adult CNS,
comprising up to 5% of its cells [37].
The origin of endogenous remyelinating cells in the adult
CNS has been subject to multiple studies (for more detail
see Franklin and Ffrench-Constant [44]). Differentiated
postmitotic oligodendrocytes are unable to rebuild myelin
sheaths [4547] and remyelination is dependent on cycling
cells [47, 48]. The notion that OPCs are the main
remyelinating cells of the adult CNS emerged from studies
showing remyelination after focal demyelination by
resident progenitor cells [49, 50]. Tissue OPCs expressing NG2
and platelet-derived growth factor receptor- on their cell
surface are mobilized in response to demyelination [49, 51
53]. Recent studies provided the definitive proof that these
cells are indeed the main remyelinating cell in the CNS
following a demyelinating injury [54, 55]. In addition,
neural precursor cells (NPCs) of the adult SVZ expressing
the embryonic polysialylated form of the neural cell
adhesion molecule (PSA-NCAM) react to inflammation
and demyelination with proliferation, and migration into the
tissue and glial differentiation (...truncated)