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ASmall Light at the end of a long tunnel Long-term magnetic resonance imaging of stem cells in neonatal ischemic injury.

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EDITORIAL
A Small Light at the End of a Long Tunnel:
Long-Term Magnetic Resonance Imaging
of Stem Cells in Neonatal Ischemic Injury
O
ur inability to track the fate of implanted neural stem
cells in living animals has been a major limitation in
the field of neural transplantation. The lack of resolution in
conventional magnetic resonance imaging (MRI) and positron emission tomography (PET) has limited our ability to
sequentially follow neural stem cells after their transplantation
in the brain. This issue is of increasing importance with the
emergence of new techniques to develop inducible pluripotent stem cells (IPSCs) that can potentially serve as patientspecific customized cell transplants. Although this goal is not
immediately available as a clinical treatment, our ability to
track the fate of grafts, migration of neural transplants, and
any potential adverse reaction to grafts in vivo will be critical
for the eventual translation as a treatment of various neurological disorders. This is of particular importance in the case
of neural transplants in young individuals and children in
whom there is enormous neuronal plasticity along with concomitant normal growth and development of the brain.
One potential method to track neural transplants is to
load neural transplants with iron so that they can be imaged
using MRI. Such an approach has many advantages as MRI
technology is readily available in most parts of the world
and can easily be used without the technological limitations
imposed by other imaging modalities such as PET, which
often require more sophisticated manpower and resources.
Obenaus and colleagues1 describe the use of iron-loaded
neural stems to successfully track neural stem cells in the
brain of neonatal and young mice using MRI over an
extended period of 1 year. This long period of imaging in
human terms is the equivalent of nearly 3 to 4 decades.
They show that iron oxide–labeled neural stem cells can be
successfully tracked after implantation into the hypoxic ischemic brain to determine sites of migration, successful
graft integration with the host, and graft-derived volume
increase in the brain tissue. They were also able to monitor
the evolution of hypoxic injury and the subsequent pathological evolution of the injury in the presence of the graft as
compared to without such grafts. These studies were validated with careful histology and immunocytochemistry at
various time points.
C 2011 American Neurological Association
232 V
Several points that were unanswered from previous
work with iron oxide labeling studies and that are relevant to clinical translation are successfully answered in this
work. First, Obenaus and colleagues1 used a 4.7Tesla magnet for these imaging studies in the young mice, which if
needed in human studies is increasingly becoming available, at least in many academic institutions. Second, they
were able to image cells without causing any obvious biological alterations to the neural grafts, a concern that had
been raised with respect to the toxicity of iron oxide labeling and repeated imaging. Third, this study further confirmed the notion which had been developed from a number of previous neonatal xenograft studies that neural
xenotransplants performed in the first few weeks of life do
not appear to need immunosuppression. This is in sharp
contrast to a large number of preclinical and clinical studies of allografts and xenografts in adults that clearly show
the need for systemic immunosuppression for successful
engraftment in the brain (for example, see Olanow and
colleagues2). Fourth, unlike iron labeling studies in adult
brain transplants, in which labeling appears to be lost
fairly rapidly, the neonatal transplant paradigm used in
this work shows that iron oxide labeling is stable and can
be used for a prolonged time to follow these xenografts in
the brain. Finally, this work also confirms findings in previous reports that neural stem cell transplants suppress the
host immune response in the neonate thus rendering stem
cell transplants particularly attractive in neonatal brain
injury, which has devastating consequences of long-term
disability and morbidity in the current clinical setting.
This study also raises a number of new questions that
need to be resolved prior to clinical translation. Can these
studies be replicated in nonhuman primates or other species with larger repertoires of brain function? Can stereological studies be used to quantitate the number of cells
that survive these transplants at various time points and
correlate it to serial imaging studies using similar stereological principles? Do xenografted cells that remain undifferentiated (50%) pose any risk of dedifferentiation or malignant transformation if the host environment is altered in
adulthood? Are xenografts into neonatal brain vulnerable
to host-mediated rejection in adulthood when exposed to
Subramanian: Long-Term MRI of Stem Cells in Neonatal Ischemic Injury
environmental stress or infections that alter cytokine levels
in the brain,3 break down the blood-brain barrier,4,5 or
cause secondary neurodegeneration?6 These questions
become easier to ask with iron oxide labeling and MRI
imaging as described by Obenaus and colleagues,1 as animals can be sequentially imaged to detect changes that are
otherwise not visualized and correlated to behavior or other
outcome measures and histology.
For neonatal hypoxic ischemic injuries, the promise
of stem cell therapies, especially if targeted at the ‘‘critical
time window’’ and at the correct location (eg, penumbra
of lesion), may provide a tangible solution to ameliorate
long-term disability and morbidity. The behavioral results
in this study and future studies that try to expand on the
present study should provide additional data on this line
of research. For the clinical neurologist, patients with neonatal hypoxic injuries, and their caregivers this study seems
to provide a small light at the end of a long tunnel.
Thyagarajan Subramanian, MD
Potential Conflicts of Interest
Nothing to report.
Departments of Neurology and Neural and Behavioral Sciences
Movement Disorders Program
The Pennsylvania State University
Milton Hershey College of Medicine
Hershey, PA
References
1.
Obenaus A, Dilmac N, Tone B, et al. Long-term magnetic
resonance imaging of stem cells in neonatal ischemic injury. Ann
Neurol 2011;69:282–291.
2.
Olanow CW, Goetz CG, Kordower JH, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s
disease. [See comment]. Ann Neurol 2003;54:403–414.
3.
Subramanian T, Pollack IF, Lund RD. Rejection of mesencephalic
retinal xenografts in the rat induced by systemic administration of
recombinant interferon-gamma. Exp Neurol 1995;131:157–162.
4.
Pollack IF, Lund RD. The blood-brain barrier protects foreign antigens
in the brain from immune attack. Exp Neurol 1990;108:114–121.
5.
Pollack IF, Lund RD, Rao K. MHC antigen expression in spontaneous and induced rejection of neural xenografts. Prog Brain Res
1990;82:129–140.
6.
Rao K, Lund RD. Optic nerve degeneration induces the expression
of MHC antigens in the rat visual system. J Comp Neurol 1993;
336:613–627.
DOI: 10.1002/ana.22379
February 2011
233
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stem, long, light, cells, end, terms, ischemia, magnetic, imagine, tunnel, injury, asmall, resonance, neonatal
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