Previous work in LMB has led the way towards the ambitious goal where stem cells can be used to replace tissue damaged by neuro-degenerative diseases that cause the loss of neurons or glial cells. Our previous studies showed that large numbers of functional dopamine neurons can be derived from mouse and human embryonic stem cells. This is the type of neurons lost in Parkinson?s patients, a disease that afflicts more than one million Americans. However the clinical potential of stem cells might be exploited in two ways: cell therapy uses their ability to self-renew and differentiate in vitro prior to transplantation but clinical benefit might also be obtained by stimulating endogenous stem cells found in adult tissues (the ?if you have them ? use them? approach). Boosting endogenous stem cells will overcome the difficulty of immune rejection and may lead to simple pharmacological strategies to slow or reverse disease. In the past year we have made significant progress towards new strategies for Parkinson?s disease and ischemia that target endogenous repair systems. This work raises the exciting possibility that general growth mechanisms, used during development can promote regeneration by boosting the patient?s own repair mechanisms in Parkinson?s disease and cerebral ischemia. We have used gain and loss of function experiments to show that fibroblast growth factor 20 (FGF-20) promotes survival and stimulates dopamine (DA) release in a calbindin-negative subset of DA neurons that are preferentially lost in Parkinson?s patients. These data suggest that elevated DA levels and neuronal protection, the two functions of most interest to Parkinson?s patients may be promoted by FGF signaling in specific dopamine neurons in the ventral midbrain. These specific dopamine neurons are also at risk in a mouse genetic model with impaired transcriptional control that develops a late-onset degenerative disease. Ischemic injury to the cerebral cortex is a significant clinical problem but because of the diffuse nature of the disease there is little hope of using cell therapy to repair these lesions. Instead we have developed strategies based on the possibility of boosting endogenous repair mechanisms that might be present in the adult brain. Adeno-associated virus (AAV) was used induce FGF2 expression after ischemic injury limited to the fronto-lateral cerebral cortex. This treatment increased the number of proliferating precursors and improved motor behavior. The occurrence of newly generated cells with characteristics of neural precursors and immature neurons was most clear at three months following AAV-FGF2 treatment and ischemia. These observations suggest that there is a long-term regenerative response that could form the basis of new therapies for cortical ischemia. Based on our increased knowledge of the molecular biology of stem cells, we have shown that combined exposure to FGF2 and ligands for the Notch receptor further increase stem cell production in vivo and enhance behavioral recovery in a model of stroke.
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| Leker, Ronen R; Soldner, Frank; Velasco, Ivan et al. (2007) Long-lasting regeneration after ischemia in the cerebral cortex. Stroke 38:153-61 |
| Chen, Hui-Ling; Pistollato, Francesca; Hoeppner, Daniel J et al. (2007) Oxygen tension regulates survival and fate of mouse central nervous system precursors at multiple levels. Stem Cells 25:2291-301 |
| International Stem Cell Initiative; Adewumi, Oluseun; Aflatoonian, Behrouz et al. (2007) Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nat Biotechnol 25:803-16 |
| Rodriguez-Gomez, Jose A; Lu, Jian-Qiang; Velasco, Ivan et al. (2007) Persistent dopamine functions of neurons derived from embryonic stem cells in a rodent model of Parkinson disease. Stem Cells 25:918-28 |
| Kittappa, Raja; Chang, Wendy W; Awatramani, Rajeshwar B et al. (2007) The foxa2 gene controls the birth and spontaneous degeneration of dopamine neurons in old age. PLoS Biol 5:e325 |
| Murase, Sachiko; McKay, Ronald D (2006) A specific survival response in dopamine neurons at most risk in Parkinson's disease. J Neurosci 26:9750-60 |
| Mallon, Barbara S; Park, Kye-Yoon; Chen, Kevin G et al. (2006) Toward xeno-free culture of human embryonic stem cells. Int J Biochem Cell Biol 38:1063-75 |
| Androutsellis-Theotokis, Andreas; Leker, Ronen R; Soldner, Frank et al. (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442:823-6 |
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