Kidney International, Vol. 68 (2005), pp. 1937–1939

Stem cell therapy for disorders

OLLE LINDVALL and ZAAL KOKAIA

Laboratory of Neurogenesis and Cell Therapy, Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, Lund, Sweden; Laboratory of Biology, Section of Restorative Neurology, Stem Cell Institute, University Hospital, Lund, Sweden; and Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund, Sweden

Stem cell therapy for human brain disorders. Transplantation of survive, reinnervate the striatum, and restore dopamine stem cells or their derivatives, and mobilization of endogenous release for up to 10 years despite an ongoing disease pro- stem cells in the adult brain, have been proposed as future ther- cess, which destroys the Parkinson’s disease patient’s own apies for various brain disorders such as Parkinson’s disease and stroke. In support, recent progress shows that neurons suitable dopamine neurons [1, 2]. Several open-label trials have for transplantation can be generated from stem cells in culture, reported clear clinical benefit [3, 4]. Some patients have and that the adult brain produces new neurons from its own even been able to withdraw L-DOPA treatment for sev- stem cells in response to injury. However, from a clinical per- eral years and resume an independent life [2]. However, spective, the development of stem cell–based therapies for brain other patients have showed only modest or no improve- diseases is still at an early stage. Many basic issues remain to be solved and we need to move forward with caution and avoid ment after grafting [5, 6], which illustrates that transplan- scientifically ill-founded trials in patients. We do not know the tation procedures are far from optimal. Taken together, best stem cell source, and research on embryonic stem cells and the clinical trials with transplantation of embryonic mes- stem cells from embryonic or adult brain or from other tissues encephalic tissue in Parkinson’s disease patients provide should therefore be performed in parallel. We need to under- proof-of-principle for the cell replacement strategy in the stand how to control stem cell proliferation and differentiation into specific cell types, induce their integration into neural net- human brain. works, and optimize the functional recovery in animal models It is unlikely that transplantation of human embry- closely resembling the human disease. All these scientific ef- onic mesencephalic tissue will become a treatment for forts are clearly justified because, for the first time, there is now large numbers of Parkinson’s disease patients. Problems real hope that we in the future can offer patients with currently with tissue availability and standardization of the graft intractable diseases effective cell-based treatments to restore brain function. lead to too much variation in functional outcome. The most important goal for cell therapy research in Parkin- son’s diease is now to develop strategies to generate large The basic principle of cell therapy is very simple: to numbers of functional dopamine neurons in preparations restore brain function that has been lost due to dam- which are standardized and quality-controlled. The stem age or disease by replacing dead cells with new healthy cell technology has the potential to provide solutions to cells through transplantation. Given the complexity of these technical issues. Results from clinical trials and an- human brain structure and function, this prospect may imal models have identified a set of requirements which seem remote. However, if cell replacement will work in probably have to be fulfilled by the stem cell-derived neu- the human brain, it could provide radical new therapies rons in order to induce marked clinical improvement after for severe neurodegenerative disorders like Parkinson’s transplantation: (1) the cells should release dopamine in disease and stroke. Whether it will work or not will de- a regulated manner, and need to have the molecular, mor- pend on, first, if the grafted neurons can survive and form phologic, and electrophysiologic properties of substantia connections in the patient’s brain and, second, if the pa- nigra dopamine neurons, which should be replaced [7]; (2) tient’s brain can integrate and use the grafted neurons. when tested prior to clinical application, the cells must be Available evidence supporting that cell therapy may able to reverse motor deficits in animal models of Parkin- work in patients with brain disorders mainly originates son’s disease resembling the symptoms in patients; (3) the from clinical trials with intrastriatal transplantation of hu- yield of cells should be sufficient to allow for 100,000 or man embryonic mesencephalic tissue, rich in postmitotic more grafted dopamine neurons to survive long-term in dopamine neurons, in Parkinson’s disease patients. These each human putamen [8]; (4)The grafted dopamine neu- studies demonstrate that grafted dopamine neurons can rons should reestablish a dense terminal network in most parts of the denervated striatum; and (5) the grafts have to become functionally integrated into host basal ganglia- C 2005 by the International Society of Nephrology thalamo-cortical neural circuitries [9].

1937 1938 Lindvall and Kokaia: Stem cell therapy for human brain disorders

Cells with at least some properties of mesencephalic host neural circuitries. A major scientific challenge is to dopamine neurons have been generated in vitro from develop strategies to promote survival of the new neu- stem cells of four different sources: embryonic stem rons formed after stroke because many of them die. cells, neural stem cells in the embryonic and adult brain, Several factors can increase adult neurogenesis by stim- and stem cells in other tissues (e.g., ) [10]. ulating formation and/or improving survival of new Currently, the most effective production of dopamine neurons [e.g., fibroblast growth factor-2 (FGF-2), epi- neurons suitable for transplantation has been reported dermal growth factor (EGF), stem cell factor, ery- from mouse embryonic stem cells [10]. Large numbers thropoietin (EPO), brain-derived neurotrophic factor of dopamine neurons can also be generated from human (BDNF), caspase inhibitors, and anti-inflammatory drugs embryonic stem cells [11], but the survival after trans- [16, 17]. Inflammation has been shown to be detrimen- plantation in animals models has been poor. A general tal for neurogenesis in the dentate gyrus [18, 19]. Be- problem with the stem cell–derived neurons described so cause stroke causes inflammation, these data suggest that far is that it we still do not know to what extent they can inflammation-mediated suppression of neurogenesis may reinnervate the denervated striatum after transplantation limit the effectiveness of neuroregenerative responses in and release dopamine in vivo, and if they can improve be- this disorder. havioural deficits resembling Parkinson’s disease motor Stem cell–based approaches for the first time offer symptoms in patients. real hope that we in the future will be able to offer It should be emphasized that the availability of virtually patients with currently intractable brain disorders effec- unlimited numbers of dopamine neurons, generated from tive treatments. However, we need to know much more stem cells, will not automatically mean that we have a about mechanisms of cell proliferation, differentiation clinically competitive cell therapy for Parkinson’s disease. and survival, and of regeneration and functional recov- We have to define better selection criteria for patients ery. Research on different sources of stem cells and on en- with respect to stage and type of disease, and determine dogenous neuroregenerative responses should continue the preoperative degeneration pattern so that we know in parallel. It is important to emphasize that the biologic what needs to be repaired. The clinical transplantation problems that have to be solved in order to develop safe procedure should be tailor-made with respect to dose and and effective stem therapies are complex and should not location of grafted cells based on preoperative imaging be underestimated. so that the repair of the dopamine system in striatum and extrastriatal areas is as complete as possible in each ACKNOWLEDGMENTS patient’s brain. The risk for teratoma from embryonic Our own research was supported by the Swedish Research Coun- stem cells, and the consequences of the introduction of cil, EU project LSHBCT-2003–503005 (EUROSTEMCELL), and the new genes in stem cell–derived neurons should also be S¨oderberg, Crafoord, and Kock Foundations. The Lund Stem Cell Cen- carefully evaluated after transplantation in experimental ter is supported by a Center of Excellence Grant in Life Sciences from the Swedish Foundation for Strategic Research. animals. Reprint requests to Olle Lindvall, M.D., Ph.D., Laboratory of Neuro- The possibility to restore brain function by transplan- genesis and Cell Therapy, Section of Restorative Neurology, Wallenberg tation of stem cells or cells predifferentiated in vitro from Neuroscience Center, University Hospital, SE-221 84 Lund, Sweden. stem cells is being explored also in stroke [10]. In addition, E-mail: [email protected] recent findings in rodents have suggested an alternative approach to cell replacement therapy in this disorder REFERENCES based on the adult brain’s ability to produce new neu- 1. KORDOWER JH, FREEMAN TB, SNOW BJ, et al: Neuropathological rons from its own neural stem cells. Stroke leads to in- evidence of graft survival and striatal reinnervation after the trans- plantation of fetal mesencephalic tissue in a patient with Parkinson’s creased generation of neurons from neural stem cells in disease. 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