Cellular repair of CNS disorders:
an immunological perspective
Zhiguo Chen and Theo D. Palmer?
Department of Neurosurgery, Stanford University School of Medicine, MSLS P304, MC5487,
1201 Welch Road, Stanford, CA 94305, USA
Received February 28, 2008; Revised February 28, 2008; Accepted March 27, 2008
Cellular repair is a promising strategy for treating central nervous system (CNS) disorders. Several strategies
have been contemplated including replacement of neurons or glia that have been lost due to injury or dis-
ease, use of cellular grafts to modify or augment the functions of remaining neurons and/or use of cellular
grafts to protect neural tissue by local delivery of growth or trophic factors. Depending on the specific dis-
ease target, there may be one or many cell types that could be considered for therapy. In each case, an
additional variable must be considered—the role of the immune system in both the injury process itself
and in the response to incoming cells. Cellular transplants can be roughly categorized into autografts, allo-
grafts and xenografts. Despite the immunological privilege of the CNS, allografts and xenografts can elicit
activation of the innate and adaptive immune system. In this article, we evaluate the various effects that
immune cells and signals may have on the survival, proliferation, differentiation and migration/integration
of transplanted cells in therapeutic approaches to CNS injury and disease.
Cellular transplantation has been considered for therapy for
more than 100 years. One of the first tissue grafting experi-
ments reported in the scientific literature was performed by
W.G. Thompson in the late nineteenth century. Dr. Thompson
transplanted pieces of neocortex from one dog to another
dog—with outcome described as ‘that the brain tissue has suf-
ficient vitality to survive for seven weeks the operation of
transplantation without wholly losing its identity as brain sub-
stance’ (1). In the intervening years, a myriad of transplan-
tation strategies have been tried in both animals and humans.
One of the most well-explored human models involves
tissue or cell transplantation for the treatment of Parkinson’s
disease (PD). The goal has been to restore the abundance of
dopamine—a chemical neural transmitter produced by the
cells that die in PD. Levo-DOPA, the precursor to dopamine,
can be taken orally and is the standard of care but the dosage
must be increased as the disease progresses and the side effects
of systemic delivery eventually outweigh the benefit. Trans-
plantation of dopamine producing cells has been pursued as
a way to produce dopamine only where needed. Various
tissue sources rich in dopamine have been used including
mesencephalic tissue (the ventral mesencephalon is the brain
region where the dopaminergic neurons affected in PD nor-
mally reside). Each tissue type has shown promise in
animals and has ultimately been tested in clinical trials.
Adrenal medulla and carotid body transplantation gave only
modest and transient improvement though this has not contin-
ued in wide spread use (2,3). In contrast, over 300 patients
have been transplanted worldwide with human fetal ventral
mesencephalic tissues. It has been shown that the transplanted
dopaminergic neurons can survive and re-innervate part of the
host striatum. Dramatic effects have been observed in some
individuals (4). As might be imagined, human fetal tissue is
not in abundant supply and it has been very difficult to stan-
dardize transplantations, and variability and potential negative
side effects have plagued this strategy [reviewed by (5)]. In a
double-blind clinical study, more than 50% of patients receiv-
ing bilateral fetal nigral transplantation developed ‘off’-
medication dyskinesia [e.g. uncontrolled movement (6)]. The
authors speculate that dopamine asymmetries across grafted
striatum, altered synapse formation and partial immune
rejection, may have caused this effect.
Alternative tissue sources are being considered for central
nervous system (CNS) transplantation. A common goal is to
gain control of the specific attributes of the transplanted
?To whom correspondence should be addressed. Tel: þ1 6507361482; Fax: þ1 6507361949; Email: email@example.com
# The Author 2008. Published by Oxford University Press. All rights reserved.
For Permissions, please email: firstname.lastname@example.org
Human Molecular Genetics, 2008, Vol. 17, Review Issue 1
by guest on December 31, 2015
cells and improve efficacy. Cellular grafts, such as those
generated from embryonic stem cells (ESCs), fetal tissue-
derived neural stem cells, adult neural stem cells, stem cells
transdifferentiated from other types of adult tissues and xeno-
geneic tissue/cell grafts may provide the consistency and
reproducibility needed for bringing transplantation therapy
into mainstream clinical use [reviewed by (7)].
Cell grafts to modify a disease or injury process
One of the most promising applications of cellular grafts in the
CNS is to use the graft to modify the disease or injury process
and thus protect from further decline of function. This can be
potentially accomplished using grafts that locally produce
growth factors or immune modifying signals. For example,
glial cell-derived neurotrophic factor (GDNF) is a potent neu-
roprotective agent for dopaminergic neurons, and GDNF infu-
sion into PD patient brains has shown early clinical efficacy
(8). As an alternative to continuous mechanical delivery,
cells have been considered as vehicles for the stable and long-
term delivery of GDNF at a transplant site. Work by Svendsen
et al. provides a good key example of this strategy using
human fetal brain tissue-derived neural stem cell cultures. In
this model, transplant of human neural progenitor cells
(hNPCs) that have been genetically engineered to produce
high levels of GDNF were introduced into the rodent and non-
human primate striatum in models of dopamine cell death
related to PD. The cells survived at least 3 months and
enhanced host dopamine cells survival and fiber outgrowth (9).
Cell transplant for disease or injury modification is also con-
sidered in spinal cord injury (SCI). Bone marrow cells are
known to modulate the microenvironment of the spinal
lesion by protecting against excitotoxicity (10), secreting
support proteins, such as brain natriuretic peptide, brain-
derived neurotrophic factor (BDNF) and GDNF (11–13).
This combination of natural modifying effects appears to
provide a permissive growth substrate for limited native regen-
eration and also suppresses the destructive inflammatory pro-
cesses that lead to sub-acute tissue loss, and animals show
reduced cavity formation and lesion volume (14). Bone
marrow cells can also be easily isolated from a patient’s
own marrow, thus avoiding any concern over tissue matching
and graft rejections.
Similar strategies are contemplated for treatment of mul-
tiple sclerosis (MS). Experimental autoimmune encephalitis
(EAE), a rodent model for MS, is often used to study the
immune brain interaction that underlies the MS disease
process. Transplantations of appropriately primed immune
cells that modify the ongoing destructive inflammatory
process have shown efficacy in animal models (15). Unexpect-
edly, even NPCs themselves appear to have immunomodula-
tory effects that can be beneficial. Pluchino et al. (16) have
injected adult NPCs directly into the brain or, curiously,
even through intravenous routes, and found that the cells
home to areas of MS lesions. At these sites, they note
reductions in immune cell content and improvements in
remyelination, mediated both by the infused NPCs and also
by enhanced activity of endogenous oligodendroglia.
Cell grafts to replace neurons or glia
Throughout the history of cellular therapy in animals and
humans, the ultimate goal has been to replace damaged
neural circuitry. This would require replacement of neurons
that were lost due to the injury or disease as well as supporting
cells such as glial and vascular cells. Such extensive remodel-
ing, however, has been very hard to achieve. In PD rodent
models, fetal tissue grafts placed into the substantia nigra—
the normal location for neurons lost in PD—failed to extend
axons to the normal target areas in the striatum and no func-
tional benefit was achieved (17). Transplantation of dopermi-
nergic cells directly into the striatum does allow the cells to
integrate and provide local doperminergic inputs, and this
has led to success in animals and variable but promising
outcome in humans. Human embryonic stem cells now
provide one of the only known alternatives for producing
human midbrain dopaminergic neurons in large numbers
without resorting to human fetal brain tissues. Relatively stan-
dardized protocols have been established to differentiate ES
cells into midbrain dopamine neural precursors and transplants
of those ES-derived cells into rodent parkinsonian models
have shown survival of tyrosine hydroxylase (TH) positive
cells and significant improvement of motor tests (18,19).
Multiple groups are progressing towards clinical trials but
much work remains to adequately control the risks that may
be associated with the use of these cultured cells—the most
important being the risk of tumor formation if the graft
contains undifferentiated hESC (20).
Many other CNS injuries or diseases accompany PD as
early targets in cellular therapy. As in PD, the goal often
focuses on replacing or augmenting neural circuit function
by adding neurons. However, other cell types in the brain
are equally important therapeutic candidates. In spinal injury
and MS, a loss of myelinating oligodendrocytes in the white
matter is one of the key features of the injury or disease
process. Transplantations of oligodendrocyte progenitor cells
have been shown effective in animal models (21,22). Until
recently, sources of renewable human oligodendrocyte pro-
genitor cells have not been readily available but Keirstead
et al. (23) have recently shown that hESC can be used to
derive human oligodendrocyte progenitor cells and that trans-
plantation of these cells into adult rat spinal cord injuries
enhances remyelination and promotes improvement of motor
function. Although still early in preclinical validation and
safety testing, Keirsted and his corporate partner Geron are
moving quickly toward clinical trials in spinal injury with
this approach [reviewed by (24)].
Human embryonic stem cells are thought to be one of the most
promising new technologies available for CNS therapies, but
the hESC lines derived from blastocysts will never provide
an exact tissue match. One issue that has remained a
concern with transplants of allogeneic tissue to the brain is
the role of immune recognition in transplant outcome and effi-
cacy. Immune processes are specialized within the brain and
differ considerably from immunological processes in the per-
iphery. Grafts of poorly matched tissue can be well tolerated.
Human Molecular Genetics, 2008, Vol. 17, Review Issue 1R85
by guest on December 31, 2015
kinase C, and protein tyrosine kinases: evidence for TRAIL induction via
the T cell receptor signaling pathway. Exp. Cell Res., 252, 96–103.
45. Jurewicz, A., Matysiak, M., Andrzejak, S. and Selmaj, K. (2006)
TRAIL-induced death of human adult oligodendrocytes is mediated by
JNK pathway. Glia, 53, 158–166.
46. Aktas, O., Smorodchenko, A., Brocke, S., Infante-Duarte, C., Schulze
Topphoff, U., Vogt, J., Prozorovski, T., Meier, S., Osmanova, V., Pohl, E.
et al. (2005) Neuronal damage in autoimmune neuroinflammation
mediated by the death ligand TRAIL. Neuron, 46, 421–432.
47. Iosif, R.E., Ekdahl, C.T., Ahlenius, H., Pronk, C.J., Bonde, S., Kokaia, Z.,
Jacobsen, S.E. and Lindvall, O. (2006) Tumor necrosis factor receptor 1 is
a negative regulator of progenitor proliferation in adult hippocampal
neurogenesis. J. Neurosci., 26, 9703–9712.
48. Wachs, F.P., Winner, B., Couillard-Despres, S., Schiller, T., Aigner, R.,
Winkler, J., Bogdahn, U. and Aigner, L. (2006) Transforming growth
factor-beta1 is a negative modulator of adult neurogenesis.
J. Neuropathol. Exp. Neurol., 65, 358–370.
49. Buckwalter, M.S., Yamane, M., Coleman, B.S., Ormerod, B.K., Chin,
J.T., Palmer, T. and Wyss-Coray, T. (2006) Chronically increased
transforming growth factor-beta1 strongly inhibits hippocampal
neurogenesis in aged mice. Am. J. Pathol., 169, 154–164.
50. Nakanishi, M., Niidome, T., Matsuda, S., Akaike, A., Kihara, T. and
Sugimoto, H. (2007) Microglia-derived interleukin-6 and leukaemia
inhibitory factor promote astrocytic differentiation of neural stem/
progenitor cells. Eur. J. Neurosci., 25, 649–658.
51. Vallieres, L., Campbell, I.L., Gage, F.H. and Sawchenko, P.E. (2002)
Reduced hippocampal neurogenesis in adult transgenic mice with chronic
astrocytic production of interleukin-6. J. Neurosci., 22, 486–492.
52. Monje, M.L., Mizumatsu, S., Fike, J.R. and Palmer, T.D. (2002)
Irradiation induces neural precursor-cell dysfunction. Nat. Med., 8,
53. Roussa, E., Wiehle, M., Dunker, N., Becker-Katins, S., Oehlke, O. and
Krieglstein, K. (2006) Transforming growth factor beta is required for
differentiation of mouse mesencephalic progenitors into dopaminergic
neurons in vitro and in vivo: ectopic induction in dorsal mesencephalon.
Stem Cells, 24, 2120–2129.
54. Siglienti, I., Chan, A., Kleinschnitz, C., Jander, S., Toyka, K.V., Gold, R.
and Stoll, G. (2007) Downregulation of transforming growth factor-beta2
facilitates inflammation in the central nervous system by reciprocal
astrocyte/microglia interactions. J. Neuropathol. Exp. Neurol., 66, 47–56.
55. Deisseroth, K., Singla, S., Toda, H., Monje, M., Palmer, T.D. and
Malenka, R.C. (2004) Excitation-neurogenesis coupling in adult neural
stem/progenitor cells. Neuron, 42, 535–552.
56. Lacmann, A., Hess, D., Gohla, G., Roussa, E. and Krieglstein, K. (2007)
Activity-dependent release of transforming growth factor-beta in a
neuronal network in vitro. Neuroscience, 150, 647–657.
57. Ge, S., Goh, E.L., Sailor, K.A., Kitabatake, Y., Ming, G.L. and Song, H.
(2006) GABA regulates synaptic integration of newly generated neurons
in the adult brain. Nature, 439, 589–593.
58. Giulian, D., Woodward, J., Young, D.G., Krebs, J.F. and Lachman, L.B.
(1988) Interleukin-1 injected into mammalian brain stimulates astrogliosis
and neovascularization. J. Neurosci., 8, 2485–2490.
59. Yong, V.W., Moumdjian, R., Yong, F.P., Ruijs, T.C., Freedman, M.S.,
Cashman, N. and Antel, J.P. (1991) Gamma-interferon promotes
proliferation of adult human astrocytes in vitro and reactive gliosis in the
adult mouse brain in vivo. Proc. Natl. Acad. Sci. USA, 88, 7016–7020.
60. Silver, J. and Miller, J.H. (2004) Regeneration beyond the glial scar. Nat.
Rev. Neurosci., 5, 146–156.
61. Chen, J., Magavi, S.S. and Macklis, J.D. (2004) Neurogenesis of
corticospinal motor neurons extending spinal projections in adult mice.
Proc. Natl. Acad. Sci. USA, 101, 16357–16362.
62. Fricker-Gates, R.A., Shin, J.J., Tai, C.C., Catapano, L.A. and Macklis,
J.D. (2002) Late-stage immature neocortical neurons reconstruct
interhemispheric connections and form synaptic contacts with increased
efficiency in adult mouse cortex undergoing targeted neurodegeneration.
J. Neurosci., 22, 4045–4056.
63. Magavi, S.S., Leavitt, B.R. and Macklis, J.D. (2000) Induction of
neurogenesis in the neocortex of adult mice. Nature, 405, 951–955.
64. Ozdinler, P.H. and Macklis, J.D. (2006) IGF-I specifically enhances axon
outgrowth of corticospinal motor neurons. Nat. Neurosci., 9, 1371–1381.
65. Hohlfeld, R., Kerschensteiner, M. and Meinl, E. (2007) Dual role of
inflammation in CNS disease. Neurology, 68, S58–S63. Discussion
66. Monje, M.L., Toda, H. and Palmer, T.D. (2003) Inflammatory blockade
restores adult hippocampal neurogenesis. Science, 302, 1760–1765.
67. Butovsky, O., Ziv, Y., Schwartz, A., Landa, G., Talpalar, A.E., Pluchino,
S., Martino, G. and Schwartz, M. (2006) Microglia activated by IL-4 or
IFN-gamma differentially induce neurogenesis and oligodendrogenesis
from adult stem/progenitor cells. Mol. Cell Neurosci., 31, 149–160.
68. Byrne, J.A., Pedersen, D.A., Clepper, L.L., Nelson, M., Sanger, W.G.,
Gokhale, S., Wolf, D.P. and Mitalipov, S.M. (2007) Producing primate
embryonic stem cells by somatic cell nuclear transfer. Nature, 450,
69. Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane,
J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R. et al. (2007)
Induced pluripotent stem cell lines derived from human somatic cells.
Science, 318, 1917–1920.
70. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda,
K. and Yamanaka, S. (2007) Induction of pluripotent stem cells from adult
human fibroblasts by defined factors. Cell, 131, 861–872.
71. Ekdahl, C.T., Claasen, J.H., Bonde, S., Kokaia, Z. and Lindvall, O. (2003)
Inflammation is detrimental for neurogenesis in adult brain. Proc. Natl.
Acad. Sci. USA, 100, 13632–13637.
72. Selmani, Z., Naji, A., Zidi, I., Favier, B., Gaiffe, E., Obert, L., Borg, C.,
Saas, P., Tiberghien, P., Rouas-Freiss, N. et al. (2008) Human leukocyte
antigen-G5 secretion by human mesenchymal stem cells is required to
suppress T lymphocyte and natural killer function and to induce
CD4þCD25highFOXP3þ regulatory T cells. Stem Cells, 26, 212–222.
73. Krampera, M., Cosmi, L., Angeli, R., Pasini, A., Liotta, F., Andreini, A.,
Santarlasci, V., Mazzinghi, B., Pizzolo, G., Vinante, F. et al. (2006) Role
for interferon-gamma in the immunomodulatory activity of human bone
marrow mesenchymal stem cells. Stem Cells, 24, 386–398.
R92 Human Molecular Genetics, 2008, Vol. 17, Review Issue 1
by guest on December 31, 2015