PS2018: Biological Psychology Library Topic: Stem Cell Therapy for Neurodegenerative Disorders Library Module: Dr Claire Gibson Overview Stem cells are immature cells with prolonged self-renewal capacity and, depending on their origin, ability to differentiate into multiple cells types or all cells of the body. Transplantation of stem cells or their derivatives, and mobilisation of endogenous stem cells within the adult brain, have been proposed as future therapies for neurodegenerative disorders. All neurodegenerative disorders share a common pathological feature of extensive cell loss leading to functional abnormalities. Studies in animal models have demonstrated that neuronal replacement and partial reconstruction of damaged neuronal circuitry is possible. Importantly, there is evidence from clinical trials that cell replacement in the diseased human brain can lead to symptomatic relief. In fact, cell transplants were first carried out in patients suffering from Parkinson’s disease over 20 years ago. However, as yet, such treatments have failed to translate into routine therapeutic use and cell replacement therapy for many neurodegenerative disorders is still at the experimental stage. It may be considered unrealistic to induce functional recovery by replacing cells lost through disease, considering the complexity of human brain structure and function. There is ongoing debate within the scientific community over ethical concerns regarding the source of stem cells and whether they do actually represent a realistic therapeutic option for neurodegenerative diseases. The aim of this module is to demonstrate how cell replacement therapy can lead to functional recovery of symptoms following neurodegenerative diseases. Where relevant, evidence from experimental and clinical studies will be discussed. We will review the current evidence for using stem cells whilst also being aware of the scientific and ethical concerns. Although a large number of studies have reported the survival and integration of transplanted cells into neural circuits the focus within this topic is the behavioural consequences of stem cell therapy. *Although the term ‘neurodegenerative disorders’ refers to many disorders the focus within this module is limited to: Parkinson’s disease, Alzheimer’s disease, Huntington’s chorea, and Stroke. Core Reading Bjorklund A & Lindvall O (2000) Cell replacement therapies for central nervous system disorders. Nature Neuroscience 3: 537-544. Defer G-L, Geny C, Ricolfi F et al. (1996) Long-term outcome of unilaterally transplanted parkinsonian patients. I. Clinical Approach. Brain 119: 41-50. Lindvall O, Kokaia Z & Martinez-Serrano A (2004) Stem cell therapy for human neurodegenerative disorders – how to make it work? Nature Medicine Volume 10 (July Supplement): S42-S50. Pluchino S, Zanotti L, Deleidi M & Martino G (2005) Neural stem cells and their use as a therapeutic tool in neurological disorders. Brain Research Reviews 48: 211-219. Sonntag K-C, Simantov R & Isacson O (2005) Stem cells may reshape the prospect of Parkinson’s disease therapy. Molecular Brain Research 134: 34-51. Further Reading These references are recommended reading. They will enable students to gain a wider appreciation of the topic and go into more depth on different aspects of the topic. You may wish to search the literature yourself to find other relevant material. You are not expected to read all these papers in full as generally it is the introduction and discussion which will be most relevant. Bjorklund A, Dunnett SB, Stenevi U, Lewis ME & Iversen SD (1980) Reinnervation of the denervated striatum by subsantia nigra transplants: functional consequences as revealed by pharmacological and sensorimotor testing. Brain Research 199: 307-333. Bjorklund A, Dunnet SB, Brundin P et al. (2003) Neural transplantation for the treatment of Parkinson’s disease. THE LANCET Neurology 2: 437-445. Dunnett SB, Bjorklund A, Stenevi U & Iversen SD (1981) Behavioural recovery following transplantation of substantia nigra in rats subjected to 6-OHDA lesions of the nigrostriatal pathway. I. Unilateral lesions. Brain Research 215: 147-161. Dunnett SB, Bjorklund A, Stenevi U & Iversen SD (1981) Behavioural recovery following transplantation of substantia nigra in rats subjected to 6-OHDA lesions of the nigrostriatal pathway. II. Bilateral lesions. Brain Research 229: 457-470. Dunnett SB, Bjorklund & Lindvall O (2001) Cell therapy in Parkinson’s disease – stop or go? Nature Reviews Neuroscience 2: 365-369. Isacson O (2003) The production and use of cells as therapeutic agents in neurodegenerative diseases. THE LANCET Neurology 2: 417-424. Lee S-T, Chu K, Park J-E et al. (2005) Intravenous administration of human neural stem cells induces functional recovery in Huntington’s disease rat model. Neuroscience Research 52: 243-249. Lindvall O, Brundin P, Widner H et al. (1990) Grafts of fetal dopaminergic neurons survive and improve motor function in Parkinson’s disease. Science 247: 574-578. Lindvall O & Kokaia A (2004) Recovery and Rehabilitation in Stroke: Stem Cells. Stroke 35 (supplement 1): 2691-2694. Piccini P, Lindvall O, Bjorklund A et al. (2000) Delayed recovery of movementrelated cortical function in Parkinson’s disease after striatal dopaminergic grafts. Annals of Neurology 48: 689–695. Rossi F & Cattaneo E (2002) Neural stem cell therapy for neurological diseases: dreams and reality. Nature Reviews in Neuroscience 3: 401-409. Study Guide: Discuss the pathology and functional consequences of the various neurodegenerative disorders in relation to cell loss. Why is cell replacement therapy considered useful following the various neurodegenerative diseases? Discuss the various sources, and ethical concerns associated with them, of stem cells? Discuss the evidence for functional improvement following cell replacement therapy (animal and human studies). What are the mechanisms underlying any functional improvements? Is the use of cell replacement therapy more justified for treatment of certain diseases compared to others? What issues remain unresolved in the application of stem cell therapy to human clinical trials?