PMID-15272269 Stem cell therapy for human neurodegenerative disorders-how to make it work.
- Before clinical trials are initiated, we need to know how to control stem cell proliferation and differentiation into specific phenotypes, induce integration into existing circuits and optimize functional recovery in animal models. (from abstract)
- It may seem untralistic, though, to induce functional recovery by replacing cells lost through disease, considering the complexity of human brain structure and function.
- Animal models have shown at least that it is possible.
- Intrastriatal transplantation of human fetal mesencephatic tissue have provided a proof of principle that neuronal replacement can work in humans; neurons survive, even as the patients own SN neurons die, for up to 10 years [1,2]. Seems they can become functionally integrated into the brain, and releive symptoms of akinesia [3].
- Sham-controlled surgieries showed modest benefit, showing that the transplantation techniques are suboptimal.
- Dyskinesias are a common side-effect in 7-15% of patients, likely due to patchy reinervation or inflammatory response to the grafted cells.
- Unlikely that this will be a common treatment, due to unavailabiltiy of the fetal tissue.
- Better bet: culture the cells in vitro.
- Requirements for graft:
- Cells should release a regulated amount of DA
- Cells must reverse PD in animal models
- at least 1e5 cells must survive in humans
- grafted cells should establish a dense terminal network throughout the striatum
- and cells should become functionally integrated into the BG.
- Debilitating symptoms in PD and related disorders are caused by pathological canges in non-dopaminergic systems (neuroplasticity hypothesis).
- For more complete reversal of Parkinson's symptoms, it may be necessary to stimulate regrowth of axons from grafts in the SNpc to the striatum, which would require modification of host migration markers / growth inhibitory mechanisms [33].
- Only embryonic stem cells have been shown to work; stem cells from the adult brain don't.
- Human ESC may have chromosomal instability.
- Only 5-10% of cells in fetal mesencelphatic grafts are dopaminergic neurons. It is not yet known whether it is favorable to implant pure DA cells or if the grant should contain other cells, like glia, specifically atrocytes, which control cell fate [18,19].
- Many different pathways to dopmaninergic ESC.
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- FACS = fluorescence-assisted cell sorting.
- To date, improvements after fetal grafts have not exceeded those found with deep brain stimulation [4,6,7], and there is no convincing evidence for the reversal of drug-resistant symptoms [4]
- Even in animals with good reinnervation improvements are only partial [27].
- Some evidence for the generation of striatal neurons in mice after a stroke -- figure 3.
- Implantation of mouse ESCs into rat striatum caused teratomas in 20% of the animals [36].
- ESCs are more likely to generate tumors when implanted in the same species that they were derived from.
Stroke:
- No notable regeneration int eh cerebral cortex.
- Targeted apoptosis of neurons in mice, leaving tissue intact, leads to reformation of cortical neurons which extend axons into the thalamus. Therefore restricted self-repair is probably due to lack of cues to trigger neurogenesis from SC.
ALS:
- Several promising lines of research, but much more basic science needs to be done regarding differentiation and delivery before treatment can be attempted.
- Protecting existing neurons from degeneration seems like a better strategy.
Synthesis:
- Much more work is required, especially the basic science of differentiation / cell survival, but it's undoubtedly worth it.
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