stem cells: (how) do they work? malcolm macleod, jen lees, emily sena, hanna vesterinen, simon...

Stem cells: (How) do they work?

Malcolm Macleod, Jen Lees, Emily Sena, Hanna Vesterinen, Simon Koblar, David Howells

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).

Classification

Stem Cells

AllogeneicAutologous

Embyonic Adult TransplantationPharmacological

mobilisation

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

Possible actions

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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

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)

Efficacy

Infarct size111 experiments, 1341 animals 29.4% (95% CI 23.6 – 35.2)

Neurobehavioural score122 experiments, 1699 animals 35.2% (95% CI 30.6 – 39.7)

Efficacy of different approaches

Dose response relationship

Infarct Volume Neurobehavioural score

Delay to treatment

Infarct Volume Neurobehavioural score

Delay to assessment of outcome

Infarct Volume Neurobehavioural score

Use of immunosuppressant

Infarct Volume Neurobehavioural score

Route of delivery

Infarct Volume Neurobehavioural score

Internal validity

• Blinded outcome assessment 24%

• Randomisation 25%

• Allocation concealment 1%

Internal validity Blinding, randomisation

Infarct Volume Neurobehavioural score

Internal validity Allocation concealment

Neurobehavioural score

External validityPublication bias

External validityCo-morbidities

Infarct Volume Neurobehavioural score

Conclusions

• Stem cell based therapies appear to improve outcome in experimental stroke

• There are some concerns about the potential impact of study quality bias

Conclusions

• Autologous cells are substantially more effective than allogeneic cells

• Delivery of stem cells via the ventricles is substantially less effective than other routes

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

Hypothesis

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