Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord
John W. McDonald, Xiao-Zhong Liu, Yun Qu, Su Liu, Shannon K. Mickey, Dorothy Turetsky, David I. Gottlieb & Dennis W. Choi
Nature Medicine December 1999 Volume 5 Number 12 pp 1410 - 1412
Transplantation approaches using cellular bridges, fetal central nervous system cells, fibroblasts expressing neurotrophin-3 , hybridoma cells expressing inhibitory protein-blocking antibodies, or olfactory nerves ensheathing glial cells transplanted into the acutely injured spinal cord have produced axonal regrowth or functional benefits. Transplants of rat or cat fetal spinal cord tissue into the chronically injured cord survive and integrate with the host cord, and may be associated with some functional improvements. In addition, rats transplanted with fetal spinal cord cells have shown improvements in some gait parameters, and the delayed transplantation of fetal raphe cells can enhance reflexes. We transplanted neural differentiated mouse embryonic stem cells into a rat spinal cord 9 days after traumatic injury. Histological analysis 25 weeks later showed that transplant-derived cells survived and differentiated into astrocytes, oligodendrocytes and neurons, and migrated as far as 8 mm away from the lesion edge. Furthermore, gait analysis demonstrated that transplanted rats showed hindlimb weight support and partial hindlimb coordination not found in 'sham-operated' controls or control rats transplanted with adult mouse neocortical cells.
of NYU Impactor that produces reliable spinal cord contusion injuries.
Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord, Brain; a Journal Of Neurology, Volume 125, Part 1, January 2002, Pages 14-21, Lu, Jike; Féron, François; Mackay-Sim, Alan; Waite, Phil M E
We demonstrated recently that transplantation of olfactory ensheathing cells from the nasal olfactory mucosa can promote axonal regeneration after complete transection of the spinal cord in adult rat. Ten weeks after transection and transplantation there was significant recovery of locomotor behaviour and restoration of descending inhibition of spinal cord reflexes, accompanied by growth of axons across the transection site, including serotonergic axons arising from the brainstem raphe nuclei. The present experiment was undertaken to determine whether olfactory ensheathing cells from the olfactory mucosa are capable of promoting regeneration when transplanted into the spinal cord 4 weeks after transection. Under general anaesthesia, thoracic spinal cord at the T10 level was transected completely in adult rats. Four weeks later, the scar tissue and cavities at the transection site were removed to create a 3-4 mm gap. Into this gap, between the cut surfaces of the spinal cord, pieces of olfactory lamina propria were placed. Ten weeks later, the locomotor activity of these animals was significantly improved compared with control animals, which received implants of either pieces of nasal respiratory lamina propria or collagen (Basso, Beattie, Bresnahan Locomotor Rating Scale scores 4.3 + 0.8, n = 6 versus 1.0 + 0.2, n = 10, respectively; P < 0.001). Ten weeks after transplantation the behavioural recovery was still improving. Regrowth of brainstem raphe axons across the transplant site was shown by the presence of serotonergic axons in the spinal cord caudal to the transection site, and by retrograde labelling of cells in the nucleus raphe magnus after injections of fluorogold into the caudal spinal cord. Neither serotonergic axons nor labelled brainstem cells were observed in the control animals. These results indicate that olfactory ensheathing cells from the nasal olfactory lamina propria have the ability to promote spinal cord regeneration when transplanted 4 weeks after complete transection. Olfactory ensheathing cells are accessible and available in the human nose; the present study further supports clinical use of these cells in repairing the human spinal cord via autologous transplantation.
A short editorial relating to the above paper: Obtaining olfactory ensheathing cells from extra-cranial sources a step closer to clinical transplant-mediated repair of the CNS? Robin J. M. Franklin, Brain, Vol. 125, No. 1, 2-3, January 1, 2002
Spinal cord regeneration induced by a voltage-gated calcium channel agonist, Neurological Research, Volume 24, Issue 7, October 2002, Pages 639-642 Unlu, Agahan; Hariharan, Nithya; Iskandar, Bermans J
Regeneration in the central nervous system (CNS) is prohibitive. This is likely due to an interplay of cellular (gene expression, growth factors) and environmental (inhibition by CNS myelin) factors. Calcium supports various intracellular functions, and multiple in vitro studies have shown a role of calcium in axonal growth. In this study, we examine the role of a calcium agonist, S(-)-Bay K 8644, in promoting or impeding CNS growth in vivo, in an effort to understand further the relationship between the voltage-gated L type calcium channel and regeneration. Using a well-established rat spinal cord model of regeneration, we have injected various doses of S(-)-Bay K 8644 (30-240 M) around the injured spinal cord. Our results demonstrate that S(-)-Bay K 8644 enhances regeneration in a dose-dependent fashion. In addition, at very specific concentrations, the same agonist has no effect on or even inhibits regeneration. We conclude that spinal regeneration is highly dependent on intracellular calcium concentration. Furthermore, depending on the dose used, the effect of calcium agonist supplementation on spinal regeneration can be supportive or inhibitory.
"Global" cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain, Proceedings Of The National Academy Of Sciences Of The United States Of America Volume 96, Issue 12, June 8, 1999, Pages 7029-7034 Yandava, B D; Billinghurst, L L; Snyder, E Y
Many diseases of the central nervous system (CNS), particularly those of genetic, metabolic, or infectious/inflammatory etiology, are characterized by "global" neural degeneration or dysfunction. Therapy might require widespread neural cell replacement, a challenge not regarded conventionally as amenable to neural transplantation. Mouse mutants characterized by CNS-wide white matter disease provide ideal models for testing the hypothesis that neural stem cell transplantation might compensate for defective neural cell types in neuropathologies requiring cell replacement throughout the brain. The oligodendrocytes of the dysmyelinated shiverer (shi) mouse are "globally" dysfunctional because they lack myelin basic protein (MBP) essential for effective myelination. Therapy, therefore, requires widespread replacement with MBP-expressing oligodendrocytes. Clonal neural stem cells transplanted at birth-using a simple intracerebroventricular implantation technique-resulted in widespread engraftment throughout the shi brain with repletion of MBP. Accordingly, of the many donor cells that differentiated into oligodendroglia-there appeared to be a shift in the fate of these multipotent cells toward an oligodendroglial fate-a subgroup myelinated up to 52% (mean = approximately 40%) of host neuronal processes with better compacted myelin of a thickness and periodicity more closely approximating normal. A number of recipient animals evinced decrement in their symptomatic tremor. Therefore, "global" neural cell replacement seems feasible for some CNS pathologies if cells with stem-like features are used.
Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration, Nature 427, 740 - 744 (19 February 2004); ,Nader Sanai, Anthny D. Tramontini, Alfredo Quinones-Hinojosa, Nicholas M. Barbaro, Nalin Gupta, Sandeep Kunwar, Michael T. Lawton, Michael W. McDermott, Andrew T. Parsa, Jose Manuel-Garcuia Verdugo, Mitchel S. Berger& Arturo Alvarez-Buyalla
The subventricular zone (SVZ) is a principal source of adult neural stem cells in the rodent brain, generating thousands of olfactory bulb neurons every day. If the adult human brain contains a comparable germinal region, this could have considerable implications for future neuroregenerative therapy. Stem cells have been isolated from the human brain, but the identity, organization and function of adult neural stem cells in the human SVZ are unknown. Here we describe a ribbon of SVZ astrocytes lining the lateral ventricles of the adult human brain that proliferate in vivo and behave as multipotent progenitor cells in vitro. This astrocytic ribbon has not been observed in other vertebrates studied. Unexpectedly, we find no evidence of chains of migrating neuroblasts in the SVZ or in the pathway to the olfactory bulb. Our work identifies SVZ astrocytes as neural stem cells in a niche of unique organization in the adult human brain.
Species differences in rats and humans An overview by Pasko Rakic in referene to a paper in Nature by Sanaii et al..
Neural progenitor cells obtained from the embryonic human forebrain were expanded
up to 10(7)-fold in culture in the presence of epidermal growth factor, basic
fibroblast growth factor, and leukemia inhibitory growth factor. When transplanted
into neurogenic regions in the adult rat brain, the subventricular zone, and
hippocampus, the in vitro propagated cells migrated specifically along the routes
normally taken by the endogenous neuronal precursors: along the rostral migratory
stream to the olfactory bulb and within the subgranular zone in the dentate
gyrus, and exhibited site-specific neuronal differentiation in the granular
and periglomerular layers of the bulb and in the dentate granular cell layer.
The cells exhibited substantial migration also within the non-neurogenic region,
the striatum, in a seemingly nondirected manner up to approximately 1-1.5 mm
from the graft core, and showed differentiation into both neuronal and glial
phenotypes. Only cells with glial-like features migrated over longer distances
within the mature striatum, whereas the cells expressing neuronal phenotypes
remained close to the implantation site. The ability of the human neural progenitors
to respond in vivo to guidance cues and signals that can direct their differentiation
along multiple phenotypic pathways suggests that they can provide a powerful
and virtually unlimited source of cells for experimental and clinical transplantation.
(requested from E. Tillot by email 26 Feb 2004)
Snyder, E.Y. (1998) Neuroscientist 4: 408-245 (a review of stem cell research)
Martinez-Serrano, A., and Bjorklund, A. (1997) Trends in Neuroscience 20: 530-538 (a review of stem cell research)
Lu, J., Feron, F. Ho, SM, Mackay-Sim, A., Waite PM Transplantationof nasal olfactory tissue promotes partial recovery in paraplegic adult rats. Brain Research (2001) 889:344-357
McDonald JW, Liu, XZ, Qu, Y., Liu S., Mickey SK, Turetsky D, et al.., Transplanted embryonic stem cells survive, differentiate, and promote recovery in injured rat spinal cord. Nat Med (1999) 5: 1410-12 (HTML version)