Thanks, Scott. Like Mike, I sometimes feel I'm wandering through a forest at midnight without a torch...
Noticed the mention of Layton & Diacrin in the article you mentioned & will have a look.
Given the authors' scepticism about the use of stem cells as a therapy for stroke, what do you make of this-
Message 14345609
- particularly the claim that "the therapy worked well in animal studies" .
I note Bjork. et al referenced this -
Sinden, J. D. et al. Recovery of spatial learning by grafts of a conditionally immortalized hippocampal neuroepithelial cell line into the ischaemia-lesioned hippocampus. Neuroscience 81, 599–608 (1997) -
but not the two I have pasted below. I have copied the Bjork. conclusion also, as it sounds mildly encouraging from an investment perspective -
"Not all CNS diseases are equally suitable targets for cell replacement therapy. The best chances for success may be in those applications where clinical efficacy is determined by a single, defined biological mechanism, such as the restoration of striatal dopaminergic neurotransmission in PD by replacement of degenerated dopaminergic neurons. Given time and effort, stem cell technology holds the promise to turn cell therapy from a highly experimental procedure into a clinically useful treatment for large numbers of patients with hitherto intractable neurodegenerative diseases. It should be emphasized, though, that we need to learn much more about the mechanisms involved in the control of cell differentiation, regeneration and functional recovery in the damaged CNS, if we are to develop rational and efficient approaches to cell-based therapies. The complexity of the biological problems involved should not be underestimated, and progress should be made with great care. We would do well to learn the lesson from the troubled path of the gene therapy field: not to promise too much too early."
cognizantcommunication.com
(lots of other abstracts there too)
Cell Transplantation, Vol. 9, pp. 153-168, 2000
Conditionally Immortalized, Multipotential and Multifunctional Neural Stem Cell Lines as an Approach to Clinical Transplantation
J. A. Gray,1,2 G. Grigoryan,2 D. Virley,1 S. Patel,2 J. D. Sinden,2 and H. Hodges1,2
1Department of Psychology, The Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK
2ReNeuron Ltd, London, UK
Experiments are described using rats with two kinds of brain damage and consequent cognitive deficit (in the Morris water maze, three-door runway, and radial maze): 1) ischemic damage to the CA1 hippocampal cell field after four-vessel occlusion (4VO), and 2) damage to the forebrain cholinergic projection system by local injection of excitotoxins to the nuclei of origin or prolonged ethanol administration. Cell suspension grafts derived from primary fetal brain tissue display a stringent requirement for homotypical cell replacement in the 4VO model: cells from the embryonic day (E)18-19 CA1 hippocampal subfield, but not from CA3 or dentate gyrus or from E16 basal forebrain (cholinergic rich) led to recovery of cognitive function. After damage to the cholinergic system, conversely, recovery of function was seen with cell suspension grafts from E16 basal forebrain or cholinergic-rich E14 ventral mesencephalon, but not with implants of hippocampal tissue. These two models therefore provided a test of multifunctionality for a clonal line of conditionally immortalized neural stem cells, MHP36, derived from the E14 "immortomouse" hippocampal anlage. Implanted above the damaged CA1 cell field in 4VO-treated adult rats, these cells (multipotential in vitro) migrated to the damaged area, reconstituted the gross morphology of the CA1 pyramidal layer, took up both neuronal and glial phenotypes, and gave rise to cognitive recovery. Similar recovery of function and restoration of species-typical morphology was observed when MHP36 cells were implanted into marmosets with excitotoxic CA1 damage. MHP36 implants led to recovery of cognitive function also in two experiments with rats with excitotoxic damage to the cholinergic system damage, either unilaterally in the nucleus basalis or bilaterally in both the nucleus basalis and the medial septal area. Thus, MHP36 cells are both multipotent (able to take up multiple cellular phenotypes) and multifunctional (able to repair diverse types of brain damage).
reneuron.com
Primary CA1 and conditionally immortal MHP36 cell grafts restore conditional discrimination learning and recall in marmosets after excitotoxic lesions of the hippocampal CA1 field
David Virley1, Rosalind M. Ridley4, John D. Sinden3, Tim R. Kershaw3, Spencer Harland5, Tahira Rashid3, Sarah French3, Peter Sowinski1,3, Jeffrey A. Gray1,3, Peter L. Lantos2 and Helen Hodges1,3
1 Departments of Psychology and 2 Neuropathology, 3 ReNeuron Ltd, Institute of Psychiatry, London, 4 Medical Research Council Comparative Cognition Team, School of Clinical Veterinary Medicine, Cambridge and 5 Department of Neurosurgery, Queen Elizabeth's Hospital, Edgbaston, Birmingham, UK
Correspondence to: Dr Helen Hodges, Department of Psychology, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK
Common marmosets (Callithrix jacchus, n = 18) were trained to discriminate between rewarded and non-rewarded objects (simple discriminations, SDs) and to make conditional discriminations (CDs) when presented sequentially with two different pairs of identical objects signifying reward either in the right or left food well of the Wisconsin General Test Apparatus. After bilateral N-methyl-D-aspartate (0.12 M) lesions through the cornu ammonis-1 (CA1) field (7 µl in five sites), marmosets showed profound impairment in recall of CDs but not SDs, and were assigned to lesion only, lesion plus CA1 grafts and lesion plus Maudsley hippocampal cell line, clone 36 (MHP36) grafts groups matched for lesion-induced impairment. Cell suspension grafts (4 µl, 15–25 000 cells/µl) of cells dissected from the CA1 region of foetal brain at embryonic day 94–96, or of conditionally immortalized MHP36 cells, derived from the H-2Kb-tsA58 transgenic mouse neuroepithelium and labelled with [3H]thymidine, were infused at the lesion sites. The lesion plus MHP36 grafts group was injected five times per week with cyclosporin A (10 mg/kg) throughout testing. Lesion, grafted and intact control marmosets (n = 4–5/group) were tested on recall of SDs and CDs learned before lesioning and on acquisition of four new CDs over a 6-month period. Lesioned animals were highly impaired in recall and acquisition of CD tasks, but recall of SDs was not significantly disrupted. Both grafted groups of marmosets showed improvement to control level in recall of CDs. They were significantly slower in learning the first new CD task, but mastered the remaining tasks as efficiently as controls and were substantially superior to the lesion-only group. Visualized by Nissl staining, foetal grafts formed clumps of pyramidal-like cells within the denervated CA1 field, or jutted into the lateral ventricles. MHP36 cells, identified by ß-galactosidase staining and autoradiography, showed neuronal and astrocytic morphology, and were distributed evenly throughout the CA1 region. The results indicate that MHP36 cell grafts are as functionally effective as foetal grafts and appear to integrate into the host brain in a structurally appropriate manner, showing the capacity to differentiate into both mature neurons and glia, and to develop morphologies appropriate to the site of migration. These findings, which parallel the facilitative effects of foetal and MHP36 grafts in rats with ischaemic CA1 damage, offer encouragement for the development of conditionally immortal neuroepithelial stem cell lines for grafting in conditions of severe amnesia and hippocampal damage following recovery from cardiac arrest or other global ischaemic episodes. |
