REGENERATIVE MEDICINE
Concise Review: Cell Therapies for Stroke and
a ABSTRACT
Department of Neurology,
UT-Health, Houston, Texas,
USA; bDepartment of
Pediatric Surgery, UT-Health,
Houston, Texas, USA
Correspondence: Sean I. Savitz,
M.D., Departments of
Neurology and Pediatric Surgery,
UT-Health, 6431 Fannin Street,
Houston, Texas 77030, USA.
Telephone: 713-500-7083;
Fax: 713-500-0692; e-mail:
sean.i.savitz@uth.tmc.edu
Received August 17, 2015;
accepted for publication
September 22, 2015; rst
published online in STEM CELLS
EXPRESS February 4, 2016;
available online without
subscription through the open
access option.
C AlphaMed Press
V
1066-5099/2016/$30.00/0
http://dx.doi.org/
10.1002/stem.2253
STEM CELLS 2016;34:537542 www.StemCells.com
Traumatic Brain Injury: Targeting Microglia
SEAN I. SAVITZ,a CHARLES S. COX JR.b
Key Words. Stem cells Stroke Microglia Brain injuries
We present a model hypothesis of how several types of cell therapies may target microglia as
one of the principal cell types contributing to the inammatory response after brain injury and
discuss how imaging of brain inammation could potentially be applied to develop biomarkers
in patients with stroke and TBI enrolled into stem cell clinical trials. STEM CELLS 2016;34:537
542
Cellular therapies are advancing from bench to
clinical studies for acute neurological disorders
such as ischemic stroke, brain hemorrhage,
and traumatic brain injury (TBI). Over two dec-
ades ago, the main intentions of using stem
cells were to promote cell replacement and
restore neural connections that were damaged
after central nervous system injury. A surge of
experimental data in the past few years now
supports an entirely different paradigm in
which cell therapies modulate the immune
response to injury, reduce secondary neuronal
degeneration, and enhance endogenous repair
processes. Recent published studies are now
converging around microglia, which is a well-
known mediator of brain inammation, as one
of the principal cell types modulated by differ-
ent types of cell therapies. As we learn more
about the specic mechanisms involved, suc-
cessful translation of cell therapies for acute
brain disorders will require identifying bio-
markers of activity in patients. We present a
model hypothesis of how several types of cell
therapies may target microglia as one of the
principal cell types contributing to the inam-
matory response after brain injury and discuss
how imaging of brain inammation could
potentially be applied to develop biomarkers
in patients with stroke and TBI enrolled into
stem cell clinical trials.
INFLAMMATORY RESPONSE
After stroke and traumatic brain injury (TBI),
there is a brisk inammatory response orches-
trated by immune cells originating from
peripheral tissues and from within the brain
[1]. Sequential but overlapping phases of
immune cells from the periphery inltrate the
brain parenchyma including lymphocytes, neu-
trophils, and monocytes [2], all of which can
exacerbate on-going neuronal damage after an
acute brain injury. In the periphery, the spleen
contracts and, as a reservoir of white blood
cells, releases a number of different inamma-
tory cells and cytokines that invade and cause
further injury in the brain [35]. Microglia,
which derive from both resident cells in the
brain and inltrating monocytes, also become
activated, migrate to injured areas, and exert
dual effects depending on their phenotype.
Microglia that assume a TH-1 phenotype
release proinammatory cytokines and oxida-
tive mediators that are detrimental to surviv-
ing neurons (M1) while microglia assuming a
TH-2 phenotype tend to release neurotrophic
factors, prevent neuronal death, and promote
brain repair (M2) [6]. Activated microglia also
links with the peripheral immune response as
they can direct circulating lymphocytes to the
brain. Loane et al. demonstrated that the pro-
gressive neurodegenerative response to trau-
matic brain injury is associated with chronic
microglial activation [7]. The chronic microglial
activation was associated with myelin loss up
to 1 year post-injury. These data are important
because the chronic inammatory response
has been ignored as a therapeutic target,
despite the fact that chronic white matter loss
has been documented in post-injury patients
and the degree of tissue loss is inversely corre-
lated with neurocognitive outcomes [810].
STEM CELLS AND THEIR EFFECTS ON
INFLAMMATION AND THE SPLEEN
Various types of cell therapies have been
found to reduce neurological decits and
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538
Figure 1. Untreated adult traumatic brain injury. These white
matter (WM) ber tracts show a progressive loss of both the
number and fractional anisotropy (myclin integrity from 1 month
to 6 months post-injury). This is obvious volumetric loss com-
pared with the normal brain above. This patient in our adult
Phase 2 BMMNC trial was in the untreated control arm of the
study. The subsequent rostra/caudal view is the same patient
demonstrating progressive WM loss centrally in the corpus cal-
losum. Abbreviation: BMMNC, bone marrow-mononuclear cells;
TBI, traumatic brain injury.
modulate both the peripheral and central components of
inammation in models of stroke and TBI [1116]. In 2006,
Vendrame et al. found that the intravenous delivery of umbili-
cal cord cells in a rodent stroke model migrate to the spleen,
restore splenic size, and prevent T cell mobilization from the
spleen [17]. It was then subsequently conrmed that bone
marrow derived hematopoietic stem cells exert similar effects,
attenuating tumor necrosis factor-a and interleukin (IL)-1b
upregulation in the spleen, reducing immune cell inltration
into the brain, and decreasing activated microglia [18]. We
found similar results infusing bone marrow-derived multipo-
tent adult progenitor cells (MAPCs) after TBI in rodents.
MAPCs localized to the spleen (restoring splenic mass), and
the spleen was an important target tissue to achieve the neu-
roprotective effects of MAPC infusion [19]. There was a dose-
dependent efux of IL-4 and -10 cytokines that inuence
migration toward the M2 microglial phenotype [19]. In animal
models of stroke, we have found similar effects of MAPCs
altering the inammatory responses from the spleen [20].
Intravenous administration of even neural stem cells can
reduce inammatory responses within the spleen and inam-
matory inltrates within the brain in a rodent model of brain
hemorrhage while splenectomy abolishes these effects [21].
MICROGLIA AS THE END TARGET
Our research groups have been studying how interrupting the
splenic inammatory response is a critical mechanism underly-
ing how certain types of cell therapies promote recovery after
acute brain injury. In TBI, we have found that intravenously
administered bone marrow-derived MAPCs accumulate in the
spleen, restore splenic mass, reduce proinammatory and
increase anti-inammatory cytokines from the spleen, and
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V STEM CELLS
Stem Cell Targets in Stroke
preserve the BBB [19]. Furthermore, IV administration of
MAPCs changes peri-lesional ratios against proinammatory
(CD86 1 M1) microglia/macrophages in favor of anti-
inammatory (CD206 1 M2) microglia/macrophages. Cell-to-
cell contact between MAPCs and splenocytes leading to the
release of soluble factors and T regulatory cells appear to be
necessary for MAPCs to modulate activated microglia in the
brain [19]. Other cell therapies can selectively change the
microglial populations by promoting apoptosis of the M1 phe-
notypes, as has been reported with bone marrow mononu-
clear cells [15]. Furthermore, intravenous administration of
umbilical cord cells reduce activated microglia as well after
stroke [22]. Even intracranial injection of certain types of cell
therapies supports the hypothesis that microglia are an
important target. For example, Ohtaki et al. reported that
intracerebral injection of human bone marrow stromal cells
leads to an activation of M2-like neuroprotective microglia in
a model of global cerebral ischemia [23].
MICROGLIAL IMAGING
As preclinical studies continue to decipher further mecha-
nisms of the immunomodulatory effects of cell therapies,
much more attention is now needed to understand the bio-
logical effects of cell therapies in neurological patients
enrolled into clinical trials. Using positron emission tomogra-
phy (PET) imaging, for example, it is possible to measure
microglial activation in patients with neurological disorders.
When microglia becomes activated, it expresses a cholesterol
transporter protein (TSPO) on the outer mitochondrial mem-
brane. Radioligands have been developed that bind to TSPO
which can be used to visualize activated microglia on PET
imaging. 11C-PK11195 is the most widely used ligand for PET
imaging of microglia in patients with neurological disorders.
However, many additional radioligands with better specicity
and pharmacokinetics have been developed for clinical testing
[24]. 11C-PBR28 is a second generation TSPO radioligand that
has a greater signal-to-noise ratio than rst generation
ligands. One limitation of this ligand is the known genetic
polymorphism for the TSPO that affects radioligand binding.
Yoder et al. identied this SNP (rs6971) with the human TSPO
gene that determines whether individuals express the high,
low, or mixed afnity phenotype of TSPO. The signicance of
these data is that studies utilizing this tracer must account for
the patients TSPO genotype to interpret the microglial activa-
tion status [2527]. Testing for this single-nucleotide polymor-
phism (SNP) is readily available and cost-effective (less than
100 USD and minimally invasive). Animal and human studies
using immunohistochemistry have validated that TSPO binding
correlates with activated microglia in stroke [28, 29], TBI, and
other neurological disorders. A wealth of human studies have
conrmed that microglia become activated in areas not only
proximal to primary injured sites but also in remote areas of
the brain distal from the primary lesion [30].
LINK BETWEEN MICROGLIA AND DEGENERATION OF THE GREY
AND WHITE MATTER
Imaging microglia and other aspects of neuroinammation
may become particularly important because brain trauma
Savitz and Cox 539

Figure 2. Traumatic brain injury (TBI) induces transporter protein (TSPO) staining in the ipsilateral hippocampus. (A): Photomicrograph
of a control slice at 28 days post injury (23). (B): Photomicrograph of thalamus of a control slice at 28 days post injury (203). Inset at
CA3 region of hippocampus (ipsilateral to injury) (203). (C): Photomicrograph of a TBI slice at 28 days post injury (23). (D): Photomicro-
graph of thalamus of a TBI slice at 28 days post injury (203). (E): Graph of presence of TSPO 1 staining in thalamus in control versus
TBI. Abbreviations: CA, cornu ammonis; TBI, traumatic brain injury; TSPO, transporter protein.

causes ongoing and progressive degeneration over time.
White matter tracts are selectively vulnerable to continued
structural damage after trauma (Fig. 1). Microglia may be one
of the major cell types contributing to progressive injury as
they remain after TBI for up to 1 year within white matter
tract regions of the corpus callosum and other areas [31]. His-
tological analyses have shown that activated microglia in the
chronic stages of injury express markers of neurotoxic M1
phenotypes at the edges of expanding cortical lesions rather
than M2 phenotypes, suggesting a predominance of M1 over
M2 cell types at chronic time points after injury. Rao et al.
demonstrated that TSPO binding of 11C PK11195 in microglia/
macrophages localized to the ipsilateral hippocampus and
thalamus as a function of time. These authors note the dual-
ity of the inammatory response that can be adaptive and
protective in controlled, limited intensity, but if prolonged or
amplied, the microglial response can be associated with
progressive neuronal loss. They hypothesize that increased
TSPO expression on microglia serves to enhance protective
neurosteroidogenesis that serves to promote neuronal sur-
vival. However, they noted an association with increased neu-
ronal cell loss adjacent to the TSPO upregulated microglia
(activated). We have replicated their data using the same con-
trolled cortical impact injury model in rodents, but with an
anti-PBR Ab (Fig. 2). Human autopsy studies have veried
that neuroinammation persists for months to years after TBI;
activated microglia can be found in white matter regions asso-
ciated with axonal degeneration and in the thalami coinciding
with neuronal degeneration. PET imaging in patients indeed
conrms increased PK11195 labeling in various cortical and
subcortical regions of the brain remote from the focal injury
11 months to 17 years after TBI and that microglial activation
correlated inversely with level of consciousness,. These
studies strongly support the idea that chronic inammation

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540 Stem Cell Targets in Stroke

contributes to functional neurological outcomes after acute

Figure 3. In a phase 1 trial, 10 pediatric patients with traumatic
brain injury were treated with autologous bone marrow mononu-
clear cells. Conventional magnetic resonance imaging volumetry was
performed at 1 month (scan 1) and 6 months (scan 2) postinjury.
Average volumes are shown. There is no decrease in grey matter
(GM), white matter (WM), or intracranial volume (ICV). There is no
increase in cerebrospinal uid (CSF) volume. Typically, after traumatic
brain injury, there is progressive loss of grey and white matter with
an associated increase in CSF volumes. Over years, there is a loss in
total ICV. Abbreviations: cMRI, conventional magnetic resonance
imaging; CSF, cerebrospinal uid; GM, grey matter; ICV, intracranial
volume; TBI, traumatic brain injury; WM, white matter. This gure
was republished with permission from Wolters Kluwer Health, Inc.
injuries [30].
In stroke animal models, infarcts also lead to delayed
microglial activation in areas remote from the infarct [32].
Similar to TBI, strokes involving the corticospinal tract can
lead to delayed and progressive degeneration of the white
matter corticospinal tracts (CST) over time [33]. In addition,
the thalamus undergoes delayed neurodegeneration after
cortical infarction. It is therefore not surprising that microglia
also can remain activated in the chronic stages of stroke,
which may be dependent in part on the extent of progres-
sive white matter degeneration. In patients, 2 weeks after a
stroke involving the corticospinal tracts, there is increased
microglial activation in peri-infarct areas and in the CST
within the brainstem remote from the primary injury and in
the ipsilateral thalamus [33]. However, at 6 months, micro-
glial activation decreases around the infarct but persists in
remote areas along the CST. Conversely, in strokes that do
not affect the CST, microglial activation is not observed by 6
months after injury. Persistent microglial activity along the
CST in the brainstem correlated with the extent of axonal
injury [34]. Although further studies are needed, in both TBI
and stroke, persistent microglial activation may be an impor-
tant mediator of ongoing progressive neurodegeneration
over time. Future studies will need to dene the exact causal
relationships between microglial activation and clinical
outcome.

Figure 4. By convention, the probability of the direction of water molecule diffusion in the brain is shown by red, blue, and green,
representing leftright, superiorinferior, and anteriorposterior directions, respectively. The fractional anisotropy (FA) value scales from
0 to 1, where zero mean isotropic and one means anisotropic diffusion; a lower FA indicates reduced microstructural integrity. The corti-
cal spinal tract, which courses through the rostral pons is shown by the blue color. In (A), the blue color in the ipsilesional pons is con-
taminated with red and has a lower FA, indicating microstructural damage, compared with the contralesional side. Serially, (BF)
following treatment with bone marrow mononuclear cells, the FA value of the ipsilesional pons increased which is shown by an increase
in blue coloration. These results suggest return of microstructural integrity in the pons. Photo provided by Muhammad Haque PhD who
performed the imaging analysis.

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Savitz and Cox 541

IMAGING HOW CELL THERAPIES MAY PREVENT ON-GOING
STRUCTURAL INJURY TO GREY AND WHITE MATTER
As microglia contributes to on-going secondary degeneration,
visualizing macrostructural changes in the brain could also
serve as potential biomarkers for cell therapies. In pediatric
patients with TBI, MRI studies have shown reductions in
whole brain volume (intracranial volume), grey matter, white
matter, and concomitant increases in cerebrospinal uid space
when compared with age matched controls at 1 year post-
injury [35]. Adult patients with TBI show similar degrees of
grey and white matter volume loss over a similar time frame
[7]. Several studies indicate that volumetric loss of grey and
white matter correlates strongly with functional outcomes in
TBI [8, 10]. We performed a pilot study testing intravenous
autologous bone marrow mononuclear cells in 10 pediatric
patients with acute TBI. MRI-based volumetric analyses sug-
gested that there was no volume loss in grey or white matter
and there was no increase in ventricular space at the 6-
month time point compared with the 1 month time point
post-injury (Fig. 3) [36]. We are conducting a randomized
sham control trial to verify these ndings. Therefore, struc-
tural preservation or prevention of degeneration may prove
to be a very useful imaging surrogate for certain cell therapies
applied in the acute setting of TBI.
At the microstructural level, diffusion tensor imaging,
another imaging sequence of MRI, provides information about
the direction dependent diffusion of water molecules along
white matter tracts. Fractional anisotropy (FA) derived from
DTI provides measurements of the tissue integrity of specic
white matter tracts. Reductions in FA of individual tracts cor-
relate with impairments in TBI and stroke [9, 33, 37, 38]. Fig-
ure 1 shows the progressive loss of white matter tracts on
diffusion tensor imaging of the corpus collosum in an
untreated, control TBI patient enrolled in one of our stem cell
trials. Figure 4 shows serial diffusion tensor imaging of the
corticospinal tract in a stroke patient treated with autologous
bone marrow mononuclear cells. These types of measure-
ments may prove very useful to dene biomarkers of treat-
ment effects of cell therapies.
IMPLICATIONS FOR CELL THERAPIES AS TREATMENTS FOR
CHRONIC DISABILITY DUE TO STROKE AND TBI
The foregoing discussion indicates that microglia may not only
prove to be an important target for cell therapies in acute
neurological disorders but may also be important in the
chronic stages of these disorders. The presence of persistent
microglia contributing to on-going inammation in the chronic
stages of stroke and TBI raises the prospects that cell thera-
pies might have a therapeutic role to play in these patients
months to years after injury. Even an intravenous delivery
could conceivably be effective to reduce activated microglia in
chronically disabled patients after stroke or TBI. Observational
studies are therefore needed to better address the temporal
and spatial distribution of microglial inammation and their
potential causal association with impairments in patients
chronically disabled by brain injury. The challenge for these
studies is related to the radioligand T1/2 which requires single
dose manufacturing that necessarily occurs physically adjacent
to an advanced imaging facility capable of caring for fragile
patients. Ideally, serial PET-DT MRI imaging could be per-
formed in patients after TBI or stroke. These studies would be
descriptive/observational, then interventions targeting micro-
glial activation would be tested.
ACKNOWLEDGMENTS
The work was supported by the Bentsen Stroke Center and
the NIH Grant R01-NS071127.
AUTHOR CONTRIBUTIONS
S.I.S.: conception and design, nancial support, manuscript
writing, nal approval of manuscript; C.S.C.: conception and
design, manuscript writing, nal approval of manuscript.
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
As an employee of the institution (UT-HEALTH), Dr. Savitz has
served as a site investigator in clinical trials run by industry
companies- Aldagen, Athersys, Janssen, Genentech, Pzer for
which UT-HEALTH receives payments on the basis of clinical
trial contracts. As an employee of UT-HEALTH, Dr. Savitz
serves as an investigator on clinical trials supported by NIH
grants, Lets Cure CP, the TIRR Foundation, and the Cord
Blood Registry Systems. As an employee of UT-HEALTH, Dr.
Savitz is a principal investigator on an NIH funded grant in
basic science research. As an employee of the institution
(UT-HEALTH), Dr. Savitz has served on the data safety monitor-
ing board committee for a trial sponsored by SanBio.
Whereas UT-HEALTH employs Dr. Savitz with expertise in
stroke, UT-HEALTH serves as a consultant to Neuralstem, San-
Bio, Mesoblast, ReNeuron, Lumosa, Celgene, Dart Neuro-
science, and Aldagen. All funding goes to the institution.

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