Published online before print July 24, 2003, doi: 10.1161/01.STR.0000083462.47898.DD
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(Stroke. 2003;34:2082.)
© 2003 American Heart Association, Inc.
Controversies in Stroke |
Stem Cells: Do They Replace or Stimulate?
From the University of Melbourne and National Stroke Research Institute, Austin & Repatriation Medical Centre, Melbourne, Australia.
Correspondence to Dr David Howells, University of Melbourne and National Stroke Research Institute, Austin & Repatriation Medical Center, Level 7, Department of Medicine, Heidelberg, Victoria 3084, Australia. E-mail david.howells{at}unimelb.edu.au
Key Words: regeneration • stem cells • transplantation
In 2002, more than 6000 articles were published on stem cell biology. Many argued that the importance of these cells lies in their potential to provide transplants for treatment of diseases such as stroke, Parkinson’s disease, and spinal cord injury. The fervor is such that human embryos have been cloned, despite substantial ethical concerns, with the justification that "therapeutic cloning" will provide the stem cells needed for widespread transplantation for incurable diseases.
Stem cells prepared from human bone marrow,1 neuronal progenitor cells from adult rat dentate gyrus,2 and embryonic human forebrain3 all engraft successfully within the brain parenchyma and can differentiate into neurons.2 Surprisingly these engrafted cells can migrate to join existing neural stem cell migratory pathways,1,3 and when the brain is injured, migration is redirected specifically to the site of damage.4
After stroke in rodents, stem cells derived from bone marrow induce functional recovery measured by rotarod, adhesive-removal, and modified neurologic severity score tests when implanted into striatum5 or cortex6 or after intra-arterial infusion.7 Importantly, these improvements were noted when implantation occurred up to 14 days7 after stroke, were enhanced by brain-derived neurotrophic factor,8 and were achieved when very few implanted cells expressed neural markers9 and still retained a relatively undifferentiated morphology.6 Importantly, despite marked functional improvements, the infarcts do not get smaller.5 This latter observation would appear to exclude the possibility that the stem cells secrete neuroprotective factors that enhance survival of neurons susceptible to infarction.
These observations have led to speculation that increased host plasticity rather than differentiation and integration of new neurons must account for the observed improvements.6,9
The idea of host CNS regenerative responses is not new, but their form and functional significance have remained contentious. At the start of the 20th century, Ramon y Cajal was among the first to study neurite sprouting after brain and spinal injury but decided that these host responses were aborted attempts at reconstruction of severed pathways with little functional significance. This perception changed little until the late 1960s, when Raisman observed that axons in neighboring undamaged pathways could send out additional axonal branches or "collateral sprouts" to reinnervate the septum after it had been denervated.
Interestingly, such observations of host plasticity played a key role in promoting transplantation as a treatment for neurological disease, and today intrastriatal implants of fetal dopaminergic neurons are viewed by many as a moderately successful way of alleviating the symptoms of Parkinson’s disease. However, as in stem cell transplants for stroke, there is also a body of evidence to suggest that host responses may play a significant role in the functional recovery observed after dopaminergic implants.
Autologous adrenal medullary implants in particular were enthusiastically performed in several countries. However, they have been found to be of only mild benefit in less than half of the transplanted patients, and even in patients who improved, subsequent autopsies consistently demonstrated little or no survival of adrenal grafts. The feature that seemed to best correlate with the clinical improvement in animals and man was the presence of peri-wound host dopaminergic sprouting,10 which has been shown to be a consequence of surgical injury to the striatum and dependent on neurotrophins and growth factors supplied by activated microglia and macrophages.11
Is enhancement of such host axonal sprouting responsible for stem cell–induced recovery in animal models of stroke?
It would seem prudent to conclude that although stem cell grafts to treat stroke are in their infancy, they do appear to be able to foster functional improvement in animal models of stroke. However, their mechanism of action is far from clear. Perhaps our greatest challenge will be to establish the proportional significance of all mechanisms and fine-tune our treatments to provide the greatest benefit for the victims of stroke.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.
References
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2. Gage FH, Coates PW, Palmer TD, Kuhn HG, Fisher LJ, Suhonen JO, Peterson DA, Suhr ST, Ray J. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci U S A. 1995; 92: 11879–11883.
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10. Kordower JH, Cochran E, Penn RD, Goetz CG. Putative chromaffin cell survival and enhanced host-derived TH-fiber innervation following a functional adrenal medulla autograft for Parkinson’s disease. Ann Neurol. 1991; 29: 405–412.[CrossRef][Medline] [Order article via Infotrieve]
11. Batchelor PE, Porritt MJ, Martinello P, Parish CL, Liberatore GT, Donnan GA, Howells DW. Macrophages and microglia produce local trophic gradients that stimulate axonal sprouting toward but not beyond the wound edge. Mol Cell Neurosci. 2002; 21: 436–453.[CrossRef][Medline] [Order article via Infotrieve]
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