Guangliang Ding1, Jieli Chen1, Michael Chopp1,2, Lian Li1, Tao Yan1,3, Esmaeil Davoodi-Bojd1, Qingjiang Li1, Chengcheng Cui1, Siamak P.N. Davarani1, and Quan Jiang1
1Neurology, Henry Ford Health System, Detroit, MI, United States, 2Physics, Oakland University, Rochester, MI, United States, 3Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China, People's Republic of
Synopsis
With a suture 2-hour occlusion and reperfusion
stroke model and a low dose Streptozotocin injection combined with a high fat
food diet diabetic model of young adult Wistar rats, longitudinal measurements
of MRI
demonstrated that bone marrow stromal cell treatment of stroke in type 2
diabetes mellitus rats, compared with the saline
treated control rats, not only significantly reduced blood-brain barrier
leakage and hemorrhagic spots starting from 1 week and 3 weeks after stroke
(p<0.05) measured by contrast enhanced T1WI with Gd-DTPA and identified by
SWI, respectively; but also significantly improves white matter remodeling after
stroke measured by DSI.Introduction
Treatment of stroke with bone marrow stromal
cells (BMSC) significantly reduces vascular permeability in the ischemic brain
within two weeks after stroke in non-diabetic rats
1.
Diabetes increases risk of ischemic stroke, stroke recurrence and long-term
mortality from stroke, and worsens the overall neurological outcomes after
stroke
2.
Surprisingly, BMSC therapy administered at 24h after stroke in rats with type 1
diabetes mellitus adversely increases BBB leakage and intracranial hemorrhage
two weeks after stroke
3. In the clinic, the vast majority
(90-95%) of diabetic patients have type 2 diabetes mellitus (T2DM)
4. Thus, further
investigations are therefore warranted on the effects of BMSC treatment of
stroke in T2DM subjects.
Materials
and Methods
T2DM was induced in adult
male Wistar rats. Right
middle cerebral artery occlusion (MCAo) was then induced for 2 hours using the
filament model. Rats
were treated with either BMSC at a dose of 5 million (5x10
6) cells or
an equal volume of phosphate-buffered
saline (PBS) as the vehicle via tail vein injection at 3 days after
MCAo. The treated (BMSC, n=9) and control (PBS, n=9) groups of T2DM
rats with stroke were age and body weight matched. MRI was performed with ClinScan 7T system at
one day and then weekly for 5 weeks after ischemia-reperfusion for all rats. MRI sequences included T2-weighted imaging, susceptibility
weighted imaging (SWI), diffusion spectrum imaging and contrast enhanced T1-weighted
imaging (CE-T1WI) with Gd-DTPA, as the image contrast agent.
Results
As indicated in figure 1 from two representative rats, The contrast enhanced images exhibited regions with elevated
intensity in ischemic cerebral tissue, persisted for 5 weeks after stroke in
the control T2DM rat. However, for the BMSC treated T2DM rat, hyperintensity,
excluding the ventricle, in the ischemic brain tissue was present from 1 day to
3 weeks, rapidly faded at 4 weeks, and was hardly detectable at 5 weeks after
stroke. Figure 2 shows the longitudinal SWI images from the two representative
T2DM rats with and without BMSC treatments. The SWI images exhibited much more
severe hemorrhage in the control T2DM rat than in the BMSC treated T2DM rat
during 1d to 5w after stroke. Typical MRI images of the six diffusion maps,
obtained at 5 weeks after stroke, are shown in figure 3.
According
to the quantitative measurements, as shown in figure 4, BBB disruption volumes with Gd-DTPA enhancement were significantly
smaller in the BMSC treated T2DM rats than in the control rats from 1w after
stroke. SWI demonstrated that BMSC treatment marginally reduces hemorrhagic
volumes at 5w, but significantly decreases hemorrhagic spots starting 3w, after
stroke in T2DM rats. MRI
diffusion metrics of fraction anisotropy (FA) and entropy provide complementary
information of white matter and demonstrated by the diffusion MRI
metrics starting from 2w to 5w after stroke in T2DM rat, that BMSC treatment
significantly improves white matter features compared with the PBS treated
control rats.
Discussion and Conclusion
By using histological
methods, BBB disruption and permeability rate in diabetic
animals were regionally measured shortly after stroke
from stained cerebral tissue sections, and limited to a one time measurement.
In contrast, by employing MRI in the present
study, longitudinal measurements were performed in stroke T2DM rats with or
without BMSC treatment from 1 day to 5 weeks post stroke. MRI demonstrated that, compared
with the PBS treated control rats, BMSC treatment of stroke in T2DM rats
significantly reduced BBB leakage and hemorrhagic spots starting from 1 week and
3 weeks after stroke (p<0.05) measured by CE-T1WI with Gd-DTPA and identified
by SWI, respectively; BMSC treatment also significantly improves white matter
features.
Acknowledgements
This work was
financially supported by NIH RO1 NS083078 (JC), NS064134 (QJ), AG037506 (MC),
R41 S080329 (JC), and American Heart Association (AHA) 14GRNT20460026 (JC). The
content is solely the responsibility of the authors and does not necessarily
represent the official view of the National Institutes of Health.
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