1. Stem cells: (How) do they work? Malcolm Macleod, Jen Lees, Emily Sena, Hanna Vesterinen, Simon Koblar, David Howells

2. Definition characterized by the ability to renew themselves through mitotic cell division and differentiating into a diverse range of specialized cell types. –Totipotent stem cells can differentiate into embryonic and extraembryonic cell types. Such cells can construct a complete, viable, organism. –Pluripotent stem cells are the descendants of totipotent cells and can differentiate into nearly all cells, i.e. cells derived from any of the three germ layers. –Multipotent stem cells can differentiate into a number of cells, but only those of a closely related family of cells. –Oligopotent stem cells can differentiate into only a few cells, such as lymphoid or myeloid stem cells. –Unipotent cells can produce only one cell type, their own, but have the property of self-renewal which distinguishes them from non-stem cells (e.g. muscle stem cells).

3. Classification Stem Cells Allogeneic EmbyonicAdult Autologous Transplantation Pharmacological mobilisation

4. Objectives to establish a summary estimate of the efficacy of stem cells in animal models of focal cerebral ischaemia to ascertain the circumstances of efficacy to ascertain limitations on the internal and external validity of this literature to generate hypotheses regarding how stem cell based therapies might work, if they work

5. Possible actions + =

6. Methods Systematic search of 4 on line databases Inclusion criteria: –controlled studies –reporting the efficacy of allogeneic or autologous stem cells in animal model of focal cerebral ischaemia –outcome expressed as a change in infarct size and/or neurobehavioural score; –reporting the number of animals in each group, the mean effect size and its variance. Normalised mean difference random effects meta- analysis Funnel plot, Egger regression, Trim and Fill

7. Results 4111 hits 68 publications included 46 publications reported infarct size –111 experiments –1341 animals 53 publications reported neurobehavioural outcome –122 experiments –1699 animals Median study quality score 4 (IQR 3 to 5)

8. Efficacy Infarct size 111 experiments, 1341 animals 29.4% (95% CI 23.6 – 35.2) Neurobehavioural score 122 experiments, 1699 animals 35.2% (95% CI 30.6 – 39.7)

9. Efficacy of different approaches

10. Dose response relationship Infarct VolumeNeurobehavioural score

11. Delay to treatment Infarct VolumeNeurobehavioural score

12. Delay to assessment of outcome Infarct VolumeNeurobehavioural score

13. Use of immunosuppressant Infarct VolumeNeurobehavioural score

14. Route of delivery Infarct VolumeNeurobehavioural score

15. Internal validity Blinded outcome assessment24% Randomisation25% Allocation concealment1%

16. Internal validity Blinding, randomisation Infarct VolumeNeurobehavioural score

17. Internal validity Allocation concealment Neurobehavioural score

18. External validity Publication bias

19. External validity Co-morbidities Infarct VolumeNeurobehavioural score

20. Conclusions Stem cell based therapies appear to improve outcome in experimental stroke There are some concerns about the potential impact of study quality bias

21. Conclusions Autologous cells are substantially more effective than allogeneic cells Delivery of stem cells via the ventricles is substantially less effective than other routes

22. Conclusions There are substantial differences in patterns of efficacy for structural and functional outcomes –Delay to treatment –Delay to assessment of outcome –Use of immunosuppression

23. Hypothesis + =