1. Human Multipotential Bone Marrow Stem Cells Exert Immunomodulatory Effects, Prevent Splenic Contraction, and Enhance Functional Recovery in a Rodent Model of Ischemic stroke
Bing Yang MD, Jason Hamilton PhD, Roger Strong MS, XiaoPei Xi BS, Robert Mays PhD, Sean I. Savitz MD
Neurology Department, University of Texas Medical School at Houston

2. Disclosure
Supported by a grant from Athersys to study MultiStem® in animal models of stroke

3. Background
There are no FDA proven therapies to enhance recovery from stroke
Stem cells offers a promising direction
Major mechanisms: paracrine effects such as immunomodulation
Emerging role for the spleen in stroke:
Activey contributes to ongoing injury: release inflammatory cytokines and immune cells
MultiStem® is an adherent, human pluripotent adult stem cell product derived from bone marrow.
Hypothesis: Multistem enhances recovery after stroke by immunomodulatory mechanisms involving the spleen

4. Experiments: Animals: Long-evan Rats, Male, 300-320g
Ischemic Stroke Model: MCAo/CCAo for 3 hrs
Cells dosing and route: 1.2x107/kg, iv
Timing: cells infusion at 24 hours after MCAo
Behavior test: Cylinder test
Endpoints: behavior tests up to 28 days after MCAo, lesion sizes at 28 days; serum cytokines level up to 3 day; spleen mass changes at 3 day; IL-10 gene level changes at 3 day; and splenocytes changes at 3 day;

5. * * * *
MultiStem® cell significantly improve the recovery at 28 day after MCAo, compared with saline group. *p<0.05.
n=12 each group

6. Inflammatory Cytokine Changes
IL-6, IL-1b and IL-10 increased in the serum after stroke
MultiStem® significantly reduced IL-6 and IL-1b and increased IL-10 at 3 days after treatment
Saline n=10; MultiStem® n=12; Sham n=10

7. Spleen mass changes at 3 day
MAPC
Vehicle *
p<0.05
p=0.014 **
p<0.01
p=0.005
MEAN
(mg)
838.5
636.9
815.2 SD
144.5
140.8
115.2 n 12 11 10
MCAO
Sham
Multistem
Vehicle
Vehicle
Multistem restores the splenic mass

8. At 72 hrs after treatment, TUNEL positive cells were found in the white pulp of spleen.
100x
Capsule
sinusoid
200x
MCAO+Multistem
sinusoid
Sinusoid
200x
MCAO+Vehicle

9. There are less TUNEL positive cells found in Multistem treated animals vs. Vehicle-treated animals (n=3 per group, respectively)
MCAO+MAPC
MAPC
Vehicle
MEAN 18
49.33 SD
6.63
15.15
p=0.010
400x
MCAO+Vehicle
400x

10. IL-10 and IL-4 Gene Expression in spleen* *
*p<0.05 compared with MCAo

11. Conclusion:
MultiStem® enhances recovery from stroke in a rodent model.
The mechanisms may involve upregulating anti-inflammatory pathways and downregulating pro-inflammatory pathways.
The spleen may be a potential target of Multistem’s immunomodulatory effects.

12. Thank you