Combined NSC transplantation and VPA administration improves functional recovery of hind limbs without CST axon reextension. As VPA has been shown to have effects that are likely to be beneficial to treatment of the injured CNS, such as neuroprotection (2731), induction of neuronal differentiation (26), and promotion of neurite outgrowth (32), we examined the response of SCI model mice to different combinations of VPA administration and NSC transplantation. We prepared NSCs from embryonic forebrains of 3 different Tg mouse lines ubiquitously expressing either GFP (GFP-Tg) (33), GFP and LUC (GFP.LUC-Tg), or GFP, LUC, and the diphtheria toxin (DT) receptor human heparin-binding EGF-like growth factor (TR6) (TR6.GFP.LUC-Tg) (see Methods). The expression of GFP, LUC, and TR6 in NSCs enabled us to distinguish transplanted cells from host cells, to trace the survival of transplanted cells based on LUC activity in a noninvasive fashion, and to specifically ablate transplanted cells (see below), respectively. To obtain a homogeneous population of NSCs, we used adherent monolayer culture (3436). The embryonic forebrains were dissociated and cultured with EGF and basic FGF (bFGF) (36) (Supplemental Figure 1, A and B; supplemental material available online with this article; doi:10.1172/JCI42957DS1). These cells uniformly expressed the stem cell markers Sox2 and nestin but did not express differentiation markers (Supplemental Figure 1, C and D). Under the appropriate conditions for each lineage, these NSCs differentiated into neurons, astrocytes, or oligodendrocytes (Supplemental Figure 1, E and F). NSCs from different Tg mice behaved similarly in these culture conditions (data not shown). NSCs that had been cultured and passaged 510 times in the presence of both EGF and bFGF to maintain the undifferentiated state were used for transplantation studies.

Undifferentiated NSCs were transplanted into the SCI epicenter 7 days after injury. Nontransplanted control and transplanted mice were then intraperitoneally administered VPA or saline daily for 7 days (Figure 1A), whereafter we monitored their hind limb motor function using the open field locomotor scale (BBB score) (79, 37) for 6 weeks. Remarkably, we found that the simultaneous treatment of SCI model mice with NSCs and VPA resulted in a dramatic recovery of hind limb function compared with either treatment alone (Figure 1B and Supplemental Videos 14). There were no significant differences among the data obtained from each SCI model mouse group transplanted with the 3 distinct NSCs. Functional recovery of each treated SCI model mouse reached a plateau at around 6 weeks, the level of which was sustained for more than 3 months. Since mice treated with VPA alone showed no further improvement compared with untreated mice, it is most likely that VPA affected the function of transplanted cells.

A combination of NSC transplantation and VPA administration improves functional recovery of hind limbs without CST axon reextension. (A) Schematic of the NSC transplantation and VPA injection protocol. (B) Time course of functional recovery of hind limbs after SCI. GFP-NSCs, GFP.LUC-NSCs, and TR6.GFP.LUC-NSCs were transplanted into the SCI epicenter 7 days after injury as indicated. Combined treatment with NSC transplantation and VPA administration resulted in the greatest functional recovery. Data represent mean SEM. **P < 0.001 compared with SCI models with no treatment; *P < 0.01 compared with SCI models with no treatment (repeated measures ANOVA). NSC+VPA, total n = 21. (C) Representative pictures of BDA-labeled CST fibers at 5 mm rostral and 5 mm caudal to the lesion site. BDA was injected into the motor cortices 12 weeks after SCI. 2 weeks after the injection, mice were fixed and spinal cord sections were stained. Representative results for a GFP-NSCtransplanted spinal cord are shown. Blue, Hoechst nuclear staining. Scale bar: 20 m. (D) Quantification of the labeled CST fibers in the spinal cords of intact mice, SCI mice receiving no treatment, and SCI mice undergoing combined NSC/VPA treatment. Eight 30-mthick serial parasagittal sections from individual spinal cords were evaluated. The x axis indicates specific locations along the rostrocaudal axis of the spinal cord, and the y axis indicates the ratio of the number of BDA-labeled fibers at the indicated site to that at 6 mm rostral to the lesion site (Th9). **P < 0.001 compared with SCI models without treatment; *P = 0.188 There is no significant difference in the number of BDA-labeled fibers between NSC+VPA-treated mice (blue line) and SCI model mice with no treatment (yellow line) (repeated measures ANOVA). All data shown are from at least 3 experiments in parallel conditions, with error bars representing SEM.

We next sought to determine the basis for this improvement in locomotor function. Since transplanted NSCs have been reported to play a supportive role in the reextension of injured axons (14), we analyzed whether CST axons were regenerated by anterograde labeling using biotinylated dextran amine (BDA) (6, 16, 17). Because BDA was injected into the motor cortex, only the axons of first-order neurons in the CST could be visualized (Figure 1C). In our SCI model mice, the caudal part of the injured site was completely devoid of CST axons (Figure 1, C and D), and the same was true in mice that had undergone combined NSC transplantation and VPA administration (Figure 1, C and D). These data indicated that CST axons did not reextend in mice treated with both NSCs and VPA and therefore that some other mechanism was responsible for the animals dramatic functional locomotor improvement.

Transplanted NSCs encompass the lesion site and extend their processes. Given that host CST axon reextension was not involved in the observed hind limb recovery, we decided to focus on the transplanted cells. We analyzed the migration, morphology, neuronal marker expression, and viability of these cells after coadministration with VPA. Transplant-derived cells migrated to both rostral and caudal areas and displayed processes that extended into the gray matter and dorsal funiculus within 5 weeks of transplantation (Figure 2). Between 20% and 40% of the transplanted cells were found to be surviving in the injured spinal cord after 8 weeks, and 17% still remained viable more than 1 year after transplantation (data not shown). About 20% of the surviving cells had differentiated into microtubule-associated protein 2positive (MAP2-positive) neurons with elongated processes within 5 weeks after transplantation (Figure 2, B and C, and Figure 3, E and F). Survival of the transplanted NSCs was not significantly influenced by VPA administration (Supplemental Figure 8).

Transplanted NSCs migrate from the injection site and encompass the lesion site. Representative results of GFP-NSCtransplanted SCI model mice are shown. (A) A series of immunostaining images of injured spinal cord at 6 weeks after injury. SCI mice received combination treatment with NSC transplantation and VPA administration. Specimens were picked up every 150 m and stained with anti-GFP (green) and MAP2 (not shown) antibodies and Hoechst (blue). The epicenter of the SCI is indicated (*). Scale bar: 1 mm. (B and C) Higher-magnification images of the white boxes in A. GFP-positive transplanted NSCs differentiated into MAP2-positive neurons and extended their processes. Scale bar: 50 m.

VPA promotes neuronal differentiation of transplanted NSCs. Representative results of GFP-NSCtransplanted SCI model mice are shown. (A) Confocal images of NSCs 1 week after transplantation into the injured spinal cords. Spinal cord sections from VPA-treated (+) and untreated () mice were stained with anti-GFP (green), anti-doublecortin (DCX) (immature neuronal marker, red) and anti-GFAP (magenta) antibodies, and Hoechst (blue). VPA administration resulted in an increase in the number of DCX-positive neuronal precursors among transplanted cells (lower panel). Scale bar: 20 m. (BD) The percentages of DCX-, GFAP-, and MBP-positive cells in GFP-positive transplanted cells were quantified. **P < 0.01; *P < 0.05 compared with controls (Students t test). (E) Confocal images of NSCs 5 weeks after transplantation into injured spinal cords. Spinal cord sections from VPA-treated (+) and untreated () mice were stained with anti-GFP (green), anti-MAP2 (neuronal marker, red) and anti-GFAP (magenta) antibodies, and Hoechst (blue). VPA administration increased the numbers of MAP2-positive neurons (lower panel). Scale bar: 20 m. (F and G) The percentages of cells positive for MAP2 or GFAP in GFP-positive transplanted cells in E were quantified. **P < 0.01; *P < 0.05 compared with control (Students t test). All data shown in BD, F, and G are from at least 15 confocal images of 3 individuals in parallel experiments, with error bars representing the SD.

HDAC inhibition promotes neuronal differentiation of NSCs and is critical for transplantation-induced hind limb recovery. In contrast to previous studies, which have indicated that very few transplanted NSCs differentiate into neurons in the injured CNS environment (8, 10, 11, 20), many neurons were observed in the spinal cord after coadministration with VPA. We next examined in more detail the contribution of VPA to differentiation of cultured and transplanted NSCs. To analyze differentiation in vitro, NSCs were treated with either VPA or valpromide (VPM), an amide analog of VPA that is also an antiepileptic but is not an HDAC inhibitor (24), under differentiation culture conditions. VPA enhanced histone acetylation (Supplemental Figure 2A) and promoted neuronal differentiation and neurite outgrowth of the NSCs (Supplemental Figure 3, AC); it also inhibited astrocytic and oligodendrocytic differentiation of NSCs (Supplemental Figure 3, DG). A different HDAC inhibitor, trichostatin A (TSA), also enhanced histone acetylation (Supplemental Figure 2A) and neuronal differentiation of NSCs (not shown) (26). In contrast, VPM neither enhanced histone acetylation nor induced neuronal differentiation, suggesting that HDAC inhibition has an important role in regulating fate determination in NSCs.

We then assessed the histone acetylation status and differentiation profiles of transplanted NSCs. VPA administration enhanced histone acetylation in transplanted cells in the spinal cord (Supplemental Figure 2, B and C). When we examined the differentiation status of transplanted cells 1 week after transplantation, neuronal but not glial differentiation was greatly enhanced by VPA administration (Figure 3, AD, and Supplemental Figure 4A). A similar differentiation tendency of transplanted NSCs to that at 1 week was observed at 5 weeks after transplantation: there was a dramatic increase in the number of cells positive for MAP2 (a relatively late differentiation marker of neurons in comparison with DCX) in VPA-administered mice (Figure 3, EG, and Supplemental Figure 4B). Furthermore, VPM administration to the SCI mice neither promoted neuronal differentiation nor enhanced hind limb motor function, suggesting that HDAC inhibition has an essential role in regulating fate determination of transplanted NSCs and improvement of motor function in vivo (Supplemental Figure 5, AC). In light of the above findings that the percentage of neurons generated from transplanted NSCs increased dramatically with VPA administration, whereas those of astrocytes and oligodendrocytes declined, we anticipated that these neurons would be likely to play a major role in regenerating the disrupted neuronal circuitry of the injured spinal cord.

Transplant-derived neurons reconstruct disrupted neuronal circuits in a relay manner. We next asked how the disrupted neuronal circuits were regenerated following the combined treatment with NSC transplantation and VPA administration. Wheat germ agglutinin (WGA), which can be transsynaptically transported, is one of the best known tracers of neural pathways (38). WGA protein can be transferred across synapses to second- and third-order neurons, permitting functional neuronal circuits to be tracked in the CNS. We injected WGA-expressing adenoviruses into the motor cortex of mouse brain 12 weeks after SCI. In uninjured mice, WGA was detected as intracellular granule-like structures in neurons localized in the ventral horn throughout the spinal cord (Figure 4, A and B). In untreated SCI model mice, WGA granules were almost completely absent from the caudal region below the injured site (Figure 4, A and C). Surprisingly, although we could not observe CST axonal reextension through the lesion site (Figure 1, C and D), WGA granules were clearly present in caudal large neurons located in the spinal cords of mice treated with both NSC and VPA (Figure 4, A and D). Intriguingly, moreover, transplant-derived neurons in or close to the lesion site contained WGA granules (Figure 4E), which were received from more rostral neurons. These data imply that WGA was conveyed through the lesion site to the caudal area via transplant-derived neurons. Considering this finding, together with the fact that WGA could be detected in caudal neurons without CST axonal reextension in mice that had undergone the combined treatment, it seemed conceivable that the transplant-derived neurons reconstructed the disrupted neuronal circuits, thereby acting as relays for transmitting signals between endogenous neurons whose interconnection had been abolished by the injury. In mice that received NSC transplantation alone after SCI, the percentage of WGA-positive cells among MAP2ab-positive cells in the caudal region was higher than that in untreated mice (Figure 4C) but lower than that in mice receiving combined NSC transplantation and VPA administration (Supplemental Figure 6), reflecting the degree of hind limb functional improvement (Figure 1C).

Transplant-derived neurons reconstruct disrupted neuronal circuits in a relay manner. (A) Representative pictures of WGA-labeled neuronal cell bodies located in the ventral horn at 14 weeks after SCI. Spinal cord sections were stained with anti-WGA (red) and -MAP2ab (magenta) antibodies and Hoechst (blue). Scale bar: 20 m. Intense WGA immunoreactivity was observed as intracellular granule-like structures. Left panels show the rostral area (Th4Th7), and right panels show the caudal area (Th11 to lumbar vertebra [L] 1). In uninjured mice, WGA injected into the bilateral motor cortices was transsynaptically transported to neurons in areas rostral and caudal to the injured site (top panels). In the SCI model mice that did not receive treatment, very little WGA was observed in caudal areas (middle panels). However, in spinal cords of animals that underwent dual treatment with NSC and VPA, WGA was clearly observed in neurons in the caudal areas (bottom panels). Representative results of GFP-NSCtransplanted SCI model mice are shown. (BD) The percentages of WGA-positive cells in the neurons localized in the ventral horn were quantified. **P < 0.05 (Students t test). All data shown are from at least 30 images, containing more than 600 cells, from 3 individuals (5 images per area) in parallel experiments, with error bars representing SD. (E) Representative confocal images of WGA-labeled transplant-derived MAP2-positive neurons. Sections were stained with anti-WGA (red), anti-MAP2ab (magenta) and anti-GFP (green) antibodies, and Hoechst (blue). Granule-like WGA structures (yellow arrowheads) could be seen in the GFP and MAP2abdouble-positive transplant-derived neurons. Scale bar: 10 m.

In support of the notion of a relay function for transplant-derived neurons, immunoelectron microscopy revealed that GFP-positive transplant-derived neurons received projections from endogenous neurons (Figure 5, A and B) and that the axon terminals of transplant-derived neurons made synapses with endogenous neurons localized in the ventral horn (Figure 5, CE).

Transplant-derived neurons make synapses with endogenous neurons. (A) Immunoelectron microscopy image of a sagittal section of dual-treated (GFP-NSC and VPA) injured spinal cord (rostral area). A GFP-positive dendrite (Den) made synapses with GFP-negative endogenous axon termini (At) (yellow arrowheads). Scale bar: 1 m. (B) In other rostral regions, a dendrite of a GFP-positive transplant-derived neuron made a synapse (yellow arrowheads) with the axon terminus of a GFP-negative endogenous neuron. Scale bar: 1 m. (C) Sagittal section of dual-treated (NSC and VPA) injured spinal cord (caudal area) stained with anti-GFP antibody (dark brown). The epicenter of the SCI is indicated (*). Scale bar: 500 m. (D) High-magnification image of a large neuron localized in the ventral horn in the white rectangle in C. GFP-positive transplanted neurons extended their processes toward an endogenous neuron (yellow arrowheads). Scale bar: 100 m. (E) Immunoelectron microscopy image of the boxed area in D. GFP-positive axon termini made synapses with the dendrite of a GFP-negative endogenous large neuron (yellow arrowheads). Scale bar: 1 m.

Transplanted cells contribute directly to functional recovery of hind limb movement in SCI mice. To determine whether the transplanted cells made a direct contribution to the functional recovery of hind limbs after SCI, we performed specific ablation of transplanted cells using the toxin receptormediated cell knockout (TRECK) method (Figure 6A and refs. 39, 40). For this purpose, we prepared NSCs from the embryonic forebrains of GFP.LUC Tg and TR6.GFP.LUC Tg mice (Figure 6A and Supplemental Figure 7, A and B). Almost all of the transplanted TR6.GFP.LUC-NSCs were specifically ablated following DT administration (Figure 6, B and C). Furthermore, after ablation of the transplanted cells, the BBB scores of SCI model mice that had undergone combined TR6.GFP.LUC-NSC transplantation and VPA administration declined rapidly to levels similar to those observed in untreated and VPA onlytreated mice. These results were superimposed on the graph in Figure 1B, with the observation period extended to 12 weeks after SCI, as shown in Figure 6D (for clarity, the data for GFP-NSC.VPA and GFP.LUC-NS in Figure 1B were removed). These data indicate that the transplanted cells, in the presence of VPA, made a direct and major contribution to the functional recovery of hind limb movement in SCI model mice.

Ablation of transplanted cells abolishes hind limb motor function recovery. (A) Schematic of the protocols for NSC transplantation and for detection and ablation of transplanted cells. NSCs derived from GFP.LUC- or TR6.GFP.LUC-Tg mice were transplanted into SCI model mice 1 week after injury. VPA was intraperitoneally administered every day for 1 week. Survival of transplanted cells and locomotor function of the mice were monitored weekly for 14 weeks. (B) Survival of transplanted cells was checked every week using a bioluminescence imaging system. 6 weeks after injury (5 weeks after transplantation), each mouse received 2 DT administrations. By the following week, LUC activity had completely disappeared in mice transplanted with TR6.GFP.LUC-NSCs (lower panel). (C) Sagittal sections from SCI model mice transplanted with GFP.LUC- and TR6.GFP.LUC-NSCs 2 weeks after DT injection. All transplanted cells were ablated with DT (lower panel). Scale bar: 1 mm. (D) Time course of the changes in BBB scores in SCI model mice. The hind limb function of mice that had undergone dual treatment with TR6.GFP.LUC-NSCs and VPA dropped drastically after DT administration (black line). *P < 0.0001 compared with GFP.LUC-NSCtransplanted, VPA-administered, and DT-injected SCI model mice (blue line) (repeated measures ANOVA). Data are mean SEM. VPA, n = 8; no treatment, n = 8. (E) Twelve weeks after injury, groups of SCI model mice received NMDA injections, as indicated, into the injury epicenter, to ablate local neurons in the gray matter (blue, black, and yellow lines with triangles). *P < 0.0001 compared with non-NMDAinjected mice in each group (blue, black, and yellow lines with circles) (repeated measures ANOVA). Data represent mean SEM.

Both endogenous and transplant-derived local neurons play an important role in improving hind limb motor function. It has been shown recently that local neurons in the spinal cord play an important role in spontaneous functional recovery after SCI (41, 42). In our SCI model, we also observed slight but significant spontaneous recovery of hind limb function in untreated mice, and similar levels of recovery were sustained after ablation of transplanted cells (Figure 6D). We thus hypothesized that these recoveries were attributable to endogenous local neurons in the spinal cord. Furthermore, it seemed likely that the much higher recovery observed in mice with the combined treatment but without cell ablation (Figure 6D) was effected by transplant-derived local neurons in addition to the endogenous ones. To evaluate the involvement of these local neurons in our treatment regime, we divided each treated mouse group analyzed in Figure 6D into 2 subgroups (except for the TR6.GFP.LUC-NCStransplanted only and VPA-administered only groups). The axon-sparing excitotoxin NMDA was injected at 12 weeks after SCI into the injury epicenter in the injured spinal cords of the mice in 1 subgroup for each treatment to ablate local neurons in the gray matter (4345). In uninjured mice, NMDA injections had no significant effect on hind limb function (data not shown). However, as shown in Figure 6E, NMDA injections completely reversed both spontaneous and treatment-provoked functional recovery of hind limb movement in SCI model mice, indicating that both endogenous and transplant-derived local neurons indeed play an important role in the restoration of hind limb motor function.

Originally posted here:
JCI - Neurons derived from transplanted neural stem cells ...

Ankylosing Spondilytis, is a kind of inflammatory, autoimmune disorder of unknown etiology primarily affecting the spine, axial skeleton and large proximal joints of the body, this may inturn lead to eventual fusion of the spine.It can rage from mild to progressively degenerating diseases.

Although autoimmune, 90% of the patients suffering from the condition have proved to express the presence of HLA-B27 geneotype, confirming the genetic association of the disorder. Estimates may vary but it is observed that young men between the age group 20-40 are affected. The characterization of AS is done various symptoms, three of them occur most generally and they are pain, stiffness,excessive fatigue etc. Although the symptoms are very generalized there are some telltale conditions such as severe back pain.

The current treatments include severe physiotherapy, medication and other rehabilitation approach. However with these treatment regimen the pathophysiology of the disease is not reversed neither the further progression is stopped. On the contrary, the cutting edge stem cell treatment can offer the solution for the condition. Stem cells are the original, naive cells capable of forming any cells of the same or different lineage.

Ankylosing Spondilytis is a kind of arthritis mainly affecting the spine, but sometimes other organs are also involved.

Mentioned below is case analysis of a patient who had been suffering from Ankylosing Spondilytis. And at a young age of 25 years, he was unable to walk. Now after stem cells treatment he has started walking and his quality of life has improved.

Case Study

Name of the patient:- Rahul (name is changed for privacy reasons)

Disease: Ankylosing Spondilytis

Rahul was suffering from Ankylosing Spondilytis since past 14 years. Painful joints, restricted movements and stiffness in the body was his way of life. Although Rahul doesn't have any family history of joint diseases.

Rahul's symptoms started with sudden onset of the back pain, which went on to be severe with the whole body aches, upto the extent that he could hardly walk or if he could, he started walking like an old man. Although the initial X ray analysis showed nothing, may be because practically it take several years to show changes associated with the spine. Consequently Rahul had to visit rheumatologists, who confirmed after almost 3 years that he is suffering from AS. His treatment regimen involved diet plan, some oral medications and restricted sports activities.

Continued here:
Spinal Cord Injury Treatment, Stem Cell Therapy For Spinal ...

Characterization of isolated human SHEDs and DPSCs for use in transplantation studies. Flow cytometry analysis showed that the SHEDs and DPSCs expressed a set of mesenchymal stem cell (MSC) markers (i.e., CD90, CD73, and CD105), but not endothelial/hematopoietic markers (i.e., CD34, CD45, CD11b/c, and HLA-DR) (Table 1). Like human BMSCs, both the SHEDs and DPSCs exhibited adipogenic, chondrogenic, and osteogenic differentiation as described previously (refs. 16, 17, and data not shown). The majority of SHEDs and DPSCs coexpressed several neural lineage markers: nestin (neural stem cells), doublecortin (DCX; neuronal progenitor cells), III-tubulin (early neuronal cells), NeuN (mature neurons), GFAP (neural stem cells and astrocytes), S-100 (Schwann cells), and A2B5 and CNPase (oligodendrocyte progenitor cells), but not adenomatous polyposis coli (APC) or myelin basic protein (MBP) (mature oligodendrocytes) (Figure 1A and Table 1). This expression profile was confirmed by immunohistochemical analyses (Figure 1B).

Characterization of the SHEDs and DPSCs used for transplantation. (A) Flow cytometry analysis of the neural cell lineage markers expressed in SHEDs. Note that most of the SHEDs and DPSCs coexpressed neural stem and multiple progenitor markers, but not mature oligodendrocytes (APC and MBP). (B) Confocal images showing SHEDs coexpressed nestin, GFAP, and DCX. SHEDs also expressed markers for oligodendrocyte progenitor cells (A2B5 and CNPase), but not for mature oligodendrocytes (APC and MBP). Scale bar: 10 m. (C) Real-time RT-PCR analysis of the expression of neurotrophic factors. Results are expressed as fold increase compared with the level expressed in skin fibroblasts. Data represent the average measurements for each cell type from 3 independent donors. This set of experiments was repeated twice and yielded similar results. Data represent the mean SEM. *P < 0.01 compared with BMSCs and fibroblasts (Fbs).

Flow cytometry of stem cells from humans

Next, we examined the expression of representative neurotrophic factors by real-time PCR. Both the SHEDs and DPSCs expressed glial cellderived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) at more than 3 to 5 times the levels expressed by skin-derived fibroblasts or BMSCs (Figure 1C).

We further characterized the transcriptomes of SHEDs and BMSCs by cDNA microarray analysis. This gene expression analysis revealed a 2.0-fold difference in the expression of 3,318 of 41,078 genes between SHEDs and BMSCs. Of these, 1,718 genes were expressed at higher levels in the SHEDs and 1,593 genes were expressed at lower levels (data not shown). The top 30 genes showing higher expression in the SHEDs were in the following ontology categories: extracellular and cell surface region, cell proliferation, and tissue/embryonic development (Table 2).

Functional gene classification in SHEDs versus BMSCs

SHEDs and DPSCs promoted locomotor recovery after SCI. To compare the neuroregenerative activities of human SHEDs and DPSCs with those of human BMSCs and human skin fibroblasts, we transplanted the cells into the completely transected SCs, as described in Methods, and evaluated locomotion recovery using the Basso, Beattie, Bresnahan locomotor rating scale (BBB scale) (24). Remarkably, the animals that received SHEDs or DPSCs exhibited a significantly higher BBB score during the entire observation period, compared with BMSC-transplanted, fibroblast-transplanted, or PBS-injected control rats (Figure 2A). Importantly, their superior recoveries were evident soon after the operation, during the acute phase of SCI. After the recovery period (5 weeks after the operation), the rats that had received SHEDs were able to move 3 joints of hind limb coordinately and walk without weight support (P < 0.01; Supplemental Videos 1 and 2), while the BMSC- or fibroblast-transplanted rats exhibited only subtle movements of 12 joints. These results demonstrate that the transplantation of SHEDs or DPSCs during the acute phase of SCI significantly improved the recovery of hind limb locomotor function. Since the level of recovery was similar in the SHED- and DPSC-transplanted rats, we focused on the phenotypical examination of SHED-transplanted rats to elucidate how tooth-derived stem cells promoted the regeneration of the completely transected rat SC.

Engrafted SHEDs promote functional recovery of the completely transected SC. (A) Time course of functional recovery of hind limbs after complete transection of the SC. A total of 1 106 SHEDs, DPSCs, BMSCs, or fibroblasts were transplanted into the SCI immediately after transection. Data represent the mean SEM. **P < 0.001, *P < 0.01 compared with SCI models injected with PBS. (BD) Representative images (B and C) and quantification (D) of NF-Mpositive nerve fibers in sagittal sections of a completely transected SC, at 8 weeks after SCI. Dashed lines outline the SC. Insets are magnified images of boxed areas in B and C. (D) Nerve fiber quantification, representing the average of 3 experiments performed under the same conditions. The x axis indicates specific locations along the rostrocaudal axis of the SC (3 mm rostral and caudal to the epicenter), and y axis indicates the percentage of NF-Mpositive fibers compared with that of the sham-operated SCs at the ninth thoracic spinal vertebrate (Th9) level. Data represent the mean SEM. *P < 0.05 compared with SCI models injected with PBS. Scale bars: 100 m and inset 20 m (B) and 50 m (C). Asterisks in B and C indicate the epicenter of the lesion.

SHEDs regenerated the transected corticospinal tract and raphespinal serotonergic axons. To examine whether engrafted SHEDs affect the preservation of neurofilaments, we performed immunohistochemical analyses with an antineurofilament M (NF-M) mAb, 8 weeks after transection. Compared with the PBS-treated control SCs, the SHED-transplanted SCs exhibited greater preservation of NF-positive axons from 3 mm rostral to 3 mm caudal to the transected lesion site (Figure 2, B and C; asterisk indicates epicenter). The percentages of NF-positive axons in the epicenter of the SHED-transplanted and control SCs were 35.8% 13.0% and 8.7% 3.4%, respectively, relative to sham-treated SCs (Figure 2D).

Regeneration of both the corticospinal tract (CST) and the descending serotonergic raphespinal axons is important for the recovery of hind limb locomotor function in rat SCI. We therefore examined whether these axons had extended beyond the epicenter in the SHED-transplanted SCs. The CST axons were traced with the anterograde tracer biotinylated dextran amine (BDA), which was injected into the sensorimotor cortex. The serotonergic raphespinal axons were immunohistochemically detected by a mAb that specifically reacts with serotonin (5-hydroxytryptamine [5-HT]), which is synthesized within the brain stem. We found that both BDA- and 5-HTpositive fibers extended as far as 3 mm caudal to the epicenter in the SHED-transplanted but not the control group (Figures 3 and 4). Furthermore, some BDA- and 5-HTpositive boutons could be seen apposed to neurons in the caudal stump (Figure 3D and Figure 4C), suggesting that the regenerated axons had established new neural connections. Notably, although the number of descending axons extending beyond the epicenter was small, we observed many of them penetrating the scar tissue of the rostral stump (Figure 3A and Figure 4A). The percentages of 5-HTpositive axons of the SHED-transplanted SCs at 1 and 3 mm rostral to the epicenter were 58.9% 3.9% and 78.3% 7.4% relative to sham-treated SC, respectively (Figure 4D). These results demonstrate that the engrafted SHEDs promoted the recovery of hind limb locomotion via the preservation and regeneration of transected axons, even in the microenvironment of the damaged CNS.

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Human Dental Pulp-Derived Stem Cells Promote Locomotor ...

World J Stem Cells. 2014 Apr 26; 6(2): 120133.

Venkata Ramesh Dasari, Krishna Kumar Veeravalli, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, United States

Dzung H Dinh, Department of Neurosurgery and Illinois Neurological Institute, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, United States

Correspondence to: Dzung H Dinh, MD, Department of Neurosurgery and Illinois Neurological Institute, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL 61605, United States. ude.ciu@hnidd

Telephone: +1- 309-6552642 Fax: +1-309-6713442

Received 2013 Oct 30; Revised 2014 Feb 19; Accepted 2014 Mar 11.

With technological advances in basic research, the intricate mechanism of secondary delayed spinal cord injury (SCI) continues to unravel at a rapid pace. However, despite our deeper understanding of the molecular changes occurring after initial insult to the spinal cord, the cure for paralysis remains elusive. Current treatment of SCI is limited to early administration of high dose steroids to mitigate the harmful effect of cord edema that occurs after SCI and to reduce the cascade of secondary delayed SCI. Recent evident-based clinical studies have cast doubt on the clinical benefit of steroids in SCI and intense focus on stem cell-based therapy has yielded some encouraging results. An array of mesenchymal stem cells (MSCs) from various sources with novel and promising strategies are being developed to improve function after SCI. In this review, we briefly discuss the pathophysiology of spinal cord injuries and characteristics and the potential sources of MSCs that can be used in the treatment of SCI. We will discuss the progress of MSCs application in research, focusing on the neuroprotective properties of MSCs. Finally, we will discuss the results from preclinical and clinical trials involving stem cell-based therapy in SCI.

Keywords: Spinal cord injury, Mesenchymal stem cells, Bone marrow stromal cells, Umbilical cord derived mesenchymal stem cells, Adipose tissue derived mesenchymal stem cells

Core tip: Despite our deeper understanding of the molecular changes that occurs after the spinal cord injury (SCI), the cure for paralysis remains elusive. In this review, the pathophysiology of SCI and characteristics and potential sources of mesenchymal stem cells (MSCs) that can be used in the treatment of SCI were discussed. We also discussed the progress of application of MSCs in research focusing on the neuroprotective properties of MSCs. Finally, we discussed the results from preclinical and clinical trials involving stem cell-based therapy in SCI.

Traumatic spinal cord injury (SCI) continues to be a devastating injury to affected individuals and their families and exacts an enormous financial, psychological and emotional cost to them and to society. Despite years of research, the cure for paralysis remains elusive and current treatment is limited to early administration of high dose steroids and acute surgical intervention to minimize cord edema and the subsequent cascade of secondary delayed injury[1-3]. Recent advances in neurosciences and regenerative medicine have drawn attention to novel research methodologies for the treatment of SCI. In this review, we present our current understanding of spinal cord injury pathophysiology and the application of mesenchymal stem cells (MSCs) in the treatment of SCI. This review will be more useful for basic and clinical investigators in academia, industry and regulatory agencies as well as allied health professionals who are involved in stem cell research.

See the article here:
Mesenchymal stem cells in the treatment of spinal cord ...

Tobi is a six-year-old cocker spaniel whose hind legs were paralyzed after he suffered a herniated disc in his spine. Although Tobi will never fully regain the use of his legs, he has benefitted from a clinical trial involving stem cell transplantation in dogs that is currently underway at North Carolina State University.

See video presentation: Stem cell treatments for paralyzed dogs.

Dr. Natasha Olby, professor of neurology at the NC State College of Veterinary Medicine, specializes in researching treatments for long-term paralysis in dogs. According to Dr. Olby, even in the case of severe spinal cord injury all may not be lost in terms of spinal cord function there may still be salvageable, living nerves and nerve fibers, or axons, bridging the site of the injury that could still transmit signals if they had a little help.

Obviously, researchers would love to be able to replace all the lost neurons and axons and restore normal connections in a damaged spinal cord. But that sort of treatment is not yet possible. On the other hand, targeting surviving nerves and axons that are still crossing the site of the injury and restoring their conductivity is more attainable.

Often, these damaged nerves have lost the myelin sheath, fatty material that coats axons and allows them to conduct signals. Dr. Olby wants to restore the myelin sheath to these surviving axons by taking fat cells from the patient and turning them into stem cells that can be combined with nerve cells and injected into the site of the damage, regrowing the sheath. Even though she is still in the early stages of a randomized clinical trial, the results thus far are encouraging.

Dogs like Tobi will not be the only beneficiaries of Dr. Olbys research. If the therapy produces positive results in dogs, then translating the treatment to humans is a natural next step. And in humans, even very small improvements have the capacity to radically transform quality of life.

Even if this procedure produced an effect in a person as small as giving him or her partial control of one finger, that could allow the patient to use a computer, which opens up a whole new world of possibilities in terms of communication and interaction with the outside world, Dr. Olby says.

-- Tracey Peake

Dr. Olbys research is funded by the Morris Animal Foundation and is one of the clinical trials underway in the Neurology Service within the Randall B. Terry, Jr. Companion Animal Veterinary Medical Center. For more information on the clinical trial, visit the "call for patients" web page.

Posted Feb. 14, 2012

View original post here:
CVM Stem Cell Study Benefits Dogs with Spinal Cord Injuries

Are there stem cell therapies available for spinal cord injury?

To our knowledge, no stem cell therapy has received Health Canada or U.S. Food and Drug Administration approval for treatment of spinal cord injury at this time. Patients who are researching their options may come across companies with Web sites or materials that say otherwise and offer fee-based stem cell treatments for curing this disease. Many of these claims are not supported by sound scientific evidence and patients considering these therapies are encouraged to review some of the links below before making crucial decisions about their treatment plan.

For the latest developments read our blog entrieshere.

For moreabout stem cell clinical trials for spinal cord injuryclick here. For printed version:http://goo.gl/ZpNLg)

The basis of using stem cells to treat spinal cord injury would be as a source of new cells and products that could prevent further spinal cord damage, restore nerve function, generate new nerve cells and guide the regrowth of severed nerve fibres. Stem cells have an unparalleled regenerative capacity with the flexibility to grow into hundreds of different cell types and make factors that can support a range of physiological functions. Researchers are evaluating which types of stem cells are the best for growing neurons and other support cells in the brain, and making factors that promote nerve function. They want to develop strategies that transplant the support cells that wrap myelin insulation around nerve fibres to conduct electrical signals. A steady supply of these cells grown from stem cells could be a tremendous asset for studies that are exploring how to restore nerve function across damaged spinal cords.

Two main strategies for using stem cells to treat spinal cord injury are being explored: exogenous and endogenous repair (exo meaning outside the body and endo meaning inside the body). In exogenous repair the required cells are first grown from stem cells in the laboratory and then transplanted into patients. In endogenous repair stem cells are transplanted into the patient and the outcome depends on the bodys ability to coax the stem cells to grow into the required cells. Either way, the goal is to use stem cells to improve nerve function. There are no existing therapies that are able to repair spinal cord injuries.

Many research teams around the globe are working to develop stem cell therapies for spinal cord injury. Their common goals are to identify which stem cells are best suited for the job, which signals will be able to coax them into becoming neurons or support cells, and which large scale lab methods are effective at ramping up the production of the required cells.

The discovery of neural stem cells in Canada in 1992 kindled great hope among that stem cells could someday be used to regenerate the damage caused by spinal cord injury. Until around 1998, it was believed that the brain could not repair itself by regenerating new neurons. We now know that patients who have partial lesions to the spinal cord do experience a degree of spontaneous recovery arising from the ability of the brain to reorganize new connections. These observations spurred researchers to test their theories in animal models of spinal cord injury, and the positive results have provided the proof of principle that stem cells can potentially improve function after spinal cord injury.

Stem cell research is continuing on a number of different avenues and some of the successful stops along the way have yielded early Phase 1and 2 clinical trials for spinal cord injury. These trials are very small, mostly testing the safety of putting adult stem cells into patients. The results should yield information about the viability of this kind of therapy, but further clinical trials will be required to answer the question of whether a stem cell therapy can improve nerve function. For patients, the answer to that question is still many years away.

A North American clinical trial is using adult neural stem cell injections to treat spinal cord injury. Find out morehere.

See the article here:
Spinal Cord Injury | Canadian Stem Cell Foundation

NEWARK, Calif., Jun 04, 2015 (GLOBE NEWSWIRE via COMTEX) --

StemCells, Inc. STEM, +0.00% a world leader in the research and development of cell-based therapeutics for the treatment of central nervous system diseases and disorders, announced today that it has enrolled its first subject in Cohort 2 of its Phase II Pathway Study. The study is designed to assess the efficacy of the Company's proprietary HuCNS-SC platform technology (purified human neural stem cells) for the treatment of cervical spinal cord injury. Cohort 2 will enroll 40 patients and forms the single-blinded controlled arm of the Phase II study. The primary efficacy outcome being tested in Cohort 2 is the change in motor strength of the various muscle groups in the upper extremities innervated by the cervical spinal cord.

The Pathway Study is the first clinical trial designed to evaluate both the safety and efficacy of human neural stem cells transplanted into the spinal cord of patients with cervical spinal cord injury. Traumatic injuries to the neck can damage the cervical spinal cord and result in impaired sensation and motor function of the arms, legs, and trunk, also referred to as quadriplegia. The trial has 3 cohorts. The primary Cohort is Cohort 2 which is being conducted as a randomized, controlled, single-blind Cohort and efficacy will be primarily measured by assessing motor function according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). The trial will follow the participants for one year and will enroll up to 52 subjects.

Cohort 1 of the Pathway Study is an open-label, HuCNS-SC dose-escalation arm involving six patients. Safety data from all six subjects was reviewed by an independent Data Monitoring Committee and approval was provided to commence with Cohort 2. No safety or tolerability issues were seen at any of the dosing levels. The six-month outcome from Cohort 1 will be disclosed as interim data later this year.

Cohort 3 is an optional open label Cohort targeted to enroll 6 patients. This Cohort is designed to assess safety and preliminary efficacy in patients with less severe injuries (AIS C).

"The initiation of Cohort 2 begins the next phase of our clinical efforts towards a potential breakthrough therapy for spinal cord injury," said Stephen Huhn, M.D., FACS, FAAP, Vice President, Clinical Research and Chief Medical Officer at StemCells, Inc. "This is the first blinded, controlled clinical trial to be conducted using human neural stem cells. The goal of this proof-of-concept study is to demonstrate the potential efficacy of our cells as a treatment for victims of spinal cord injury. We currently have seven sites enrolling patients and expect to reach a total of fourteen active North American sites by year end. Conducting a multi-center study on this scale should allow us to efficiently enroll the study."

The Company completed enrollment and dosing in its open-label Phase I/II study in thoracic spinal cord injury in April 2014 and has reported top-line results. Sustained post-transplant gains in sensory function were demonstrated in seven of the twelve patients. Two patients in the Phase I/II study converted from a complete injury (AIS A) to an incomplete injury (AIS B). The final results also continue to confirm the favorable safety profile of the cells and the surgical procedure.

About the Pathway Cervical Spinal Cord Injury Clinical Trial

The Company's Phase II Pathway Study, titled "Study of Human Central Nervous System (CNS) Stem Cell Transplantation in Cervical Spinal Cord Injury," will evaluate the safety and efficacy of transplanting the Company's proprietary human neural stem cells (HuCNS-SC cells), into patients with traumatic injury in the cervical region of the spinal cord. Conducted as a randomized, controlled, single-blind study, the trial will measure efficacy by assessing motor function according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). The primary efficacy outcome will focus on change in upper extremity strength. The trial will enroll approximately 52 subjects and follow the patients for 12 months post-transplant. The first cohort of six patients completed enrollment in April and was designed to establish the cell dose for onward testing in the second cohort of the study.

Information about the Company's spinal cord injury program can be found on the StemCells, Inc. website at:

Original post:
StemCells, Inc. Announces Commencement of the Second ...

DURHAM N.C. May. 27 2015 /PRNewswire-iReach/ A new study appearing today inSTEM CELLS Translational Medicinedesigned to test how stem cell injections affect primates with spinal cord injury (SCI) showed the treatments significantly improved the animals motor function recovery and promoted faster healing too. The researchers call their findings a step forward toward the goal of improving outcomes for humans with chronic SCI.

Previous research conducted by various groups had indicated stem cell treatments helped rats with SCI. But because there are distinct differences in the nervous system and immunological responses between rodents and primates it is critical to determine how effective and safe the injections might be in a non-human primate SCI model as part of the translational research required for clinical trials explained Hideyuki Okano M.D. Ph.D. of Keio University School of Medicines physiology department and a co-author of the new study.

In this study the researchers grafted neural stem/progenitor cells (NS/PCs)derived from marmoset (a type of monkey) embryonic stem cells into adult marmosets suffering from a moderately bruised spinal cord. The advantage of using common marmosets is the similarity between their nervous system and immunological responses and those of humans Dr. Okano said.

The injections were given 14 days after the SCI occurred which research shows is an optimal time window for SCI therapy as inflammation has generally subsided by then and scar tissue has not yet had time to form.(Doctors believe that an incomplete spinal cord injury such as those of the study animals offers better chance for recovery than a complete SCI injury.) The results were promising.

Eventually motor function recovery significantly improved in the transplantation group compared to a control group that did not receive stem cells reported co-author Masaya Nakamura M.D. Ph.D. of Keios Department of Orthopedic Surgery. An animal in the control group for example could not raise her hands up to head height at 12 weeks after injury when motor function almost plateaus. On the other hand at the same point in time a transplanted animalwas able to jump successfully and run so fast it was difficult for us to catch her. She could also grip a pen at 3 cm. above head-height.

In addition he added there were no signs of immune rejection or tumors which have been a side effect of some stem cell therapies.

The researchers say this study is a step forward in their goal is to improve patients with complete SCI at the chronic phase. But we believe it will require a combination of stem cell transplantation rehabilitation and pharmacological therapy with the stem cells a key part of the treatment Dr. Okano added.

This translational research using a nonhuman primate model is a critical step in eventually applying these cells to injured spinal cord in human patients said Anthony Atala M.D. Editor-in-Chief ofSTEM CELLS Translational Medicineand director of the Wake Forest Institute for Regenerative Medicine.

Continued here:
Stem Cell Treatment Speeds Up Recovery after Spinal Cord ...

John W. McDonald, M.D., Ph.D. an associate professor of neurology at the Johns Hopkins University School of Medicine and director of the International Center for Spinal Cord Injury at Kennedy Krieger Institute taps into the bodys own repair mechanisms in search of treatments for spine injury.

Stem cells allow us to address questions Ive thought about forever. These are really exciting times for the repair of the nervous system, because we can move beyond mere correlation and get definitive answers.

Despite what I was taught in medical school, nervous system cells do divide and grow. Not all of them. But oligodendrocytes are the most prominent ones that do. If we were to follow newly born cells in an adult human brain for an hour, the majority of those cells would go on to become oligodendrocytes.

Injury and the consequence of injury disrupts the turning over of cells, basically because of reduced electrical activity, which oligodendrocytes depend on for survival and myelination.

Im convinced that endogenous stem cells in the spinal cordthose naturally born there by the million, every hour, even in spinal cord injured adultsrepresent an important therapeutic target.

Through the transplantation work were doing in mice, were learning a lot about the natural environment of cells in the nervous system. For example, mouse embryonic stem cells have the innate mechanism to overcome physical and chemical barriers. Their presence changes the microenvironment enough so that endogenous cells are able to cross barriers such as scars. We are working on figuring how to activate the same cues that cause those microenvironment changes without actually transplanting stem cells.

The whole nervous systemall the signaling between cellsruns by electrical activity. Were just now getting access to the imaging tools to be able to see and begin to understand it. If that ensemble of activity is disrupted by injury, what percent of connections remain, and how can we use what remains to recreate the orchestra?

New imaging methods now are confirming earlier animal studies that as much as 30 percent of connections can still remain below the level of spinal cord injury, even in the severe injury scenarios. This realizationthat we dont need to cure the nervous system, we just need partial repairis born out in people whove had bad spinal cord injuries who now can regain substantial function and even walk..

Our strategy is to maximize the physical integrity of your body so it can meet a cure halfway when a cure comes. We discovered that we can make a great impact on an individuals own spontaneous recovery by facilitating the bodys own micro-repair system.

What we do in lab is geared toward understanding these mechanisms of microrepair. We already know that myelination and birth of oligodendrocytes are incredibly dependent on electrical activity.

More here:
Stem Cell Research at Johns Hopkins Medicine: Spinal ...

SAN DIEGO -

Two years ago, Brenda Guerra's life changed forever.

"They told me that I went into a ditch and was ejected out of the vehicle," Guerra said.

The accident left the 26-year-old paralyzed from the waist down and confined to a wheelchair.

"I don't feel any of my lower body at all," she said.

Guerra has traveled from Kansas to UC San Diego to be the first patient to participate in a groundbreaking safety trial, testing stem cells for paralysis.

"We are directly injecting the stem cells into the spine," said Dr. Joseph D. Ciacci, professor of neurosurgery at UC San Diego.

The stem cells come from fetal spinal cords. The idea is when they're transplanted they will develop into new neurons and bridge the gap created by the injury by replacing severed or lost nerve connections. They did that in animals, and doctors are hoping for similar results in humans. The ultimate goal is to help people like Guerra walk again.

"The ability to walk is obviously a big deal not only in quality of life issues, but it also affects your survival long-term," Ciacci said.

Guerra received her injection and will be followed for five long years. She knows it's only a safety trial, but she's hoping for the best.

Here is the original post:
Health Beat: Stem cells for paralysis: 1st of its kind study

A spinal cord injury (SCI) is an injury to the spinal cord resulting in a change, either temporary or permanent, in the cord's normal motor, sensory, or autonomic function.[1] Common causes of damage are trauma (car accident, gunshot, falls, sports injuries, etc.) or disease (transverse myelitis, polio, spina bifida, Friedreich's ataxia, etc.). The spinal cord does not have to be severed in order for a loss of function to occur. Depending on where the spinal cord and nerve roots are damaged, the symptoms can vary widely, from pain to paralysis to incontinence.[2][3] Spinal cord injuries are described at various levels of "incomplete", which can vary from having no effect on the patient to a "complete" injury which means a total loss of function.

Treatment of spinal cord injuries starts with restraining the spine and controlling inflammation to prevent further damage. The actual treatment can vary widely depending on the location and extent of the injury. In many cases, spinal cord injuries require substantial physical therapy and rehabilitation, especially if the patient's injury interferes with activities of daily life.

Research into treatments for spinal cord injuries includes controlled hypothermia and stem cells, though many treatments have not been studied thoroughly and very little new research has been implemented in standard care.

The American Spinal Injury Association (ASIA) first published an international classification of spinal cord injury in 1982, called the International Standards for Neurological and Functional Classification of Spinal Cord Injury. Now in its sixth edition, the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) is still widely used to document sensory and motor impairments following SCI.[4] It is based on neurological responses, touch and pinprick sensations tested in each dermatome, and strength of the muscles that control ten key motions on both sides of the body, including hip flexion (L2), shoulder shrug (C4), elbow flexion (C5), wrist extension (C6), and elbow extension (C7).[5] Traumatic spinal cord injury is classified into five categories on the ASIA Impairment Scale:

Dimitrijevic[6] proposed a further class, the so-called discomplete lesion, which is clinically complete but is accompanied by neurophysiological evidence of residual brain influence on spinal cord function below the lesion.[7]

Signs recorded by a clinician and symptoms experienced by a patient will vary depending on where the spine is injured and the extent of the injury. These are all determined by the area of the body that the injured area of the spine innervates. A section of skin innervated through a specific part of the spine is called a dermatome, and spinal injury can cause pain, numbness, or a loss of sensation in the relevant areas. A group of muscles innervated through a specific part of the spine is called a myotome, and injury to the spine can cause problems with voluntary motor control. The muscles may contract uncontrollably, become weak, or be completely paralysed. The loss of muscle function can have additional effects if the muscle is not used, including atrophy of the muscle and bone degeneration.

A severe injury may also cause problems in parts of the spine below the injured area. In a "complete" spinal injury, all functions below the injured area are lost. An "incomplete" spinal cord injury involves preservation of motor or sensory function below the level of injury in the spinal cord.[8] If the patient has the ability to contract the anal sphincter voluntarily or to feel a pinprick or touch around the anus, the injury is considered to be incomplete. The nerves in this area are connected to the very lowest region of the spine, the sacral region, and retaining sensation and function in these parts of the body indicates that the spinal cord is only partially damaged. This includes a phenomenon known as sacral sparing which involves the preservation of cutaneous sensation in the sacral dermatomes, even though sensation is impaired in the thoracic and lumbar dermatomes below the level of the lesion.[9] Sacral sparing may also include the preservation of motor function (voluntary external anal sphincter contraction) in the lowest sacral segments.[8] Sacral sparing has been attributed to the fact that the sacral spinal pathways are not as likely as the other spinal pathways to become compressed after injury.[9] The sparing of the sacral spinal pathways can be attributed to the lamination of fibers within the spinal cord.[9]

A complete injury frequently means that the patient has little hope of functional recovery.[citation needed] The relative incidence of incomplete injuries compared to complete spinal cord injury has improved over the past half century, due mainly to the emphasis on better initial care and stabilization of spinal cord injury patients.[10] Most patients with incomplete injuries recover at least some function.[citation needed]

Determining the exact "level" of injury is critical in making accurate predictions about the specific parts of the body that may be affected by paralysis and loss of function. The level is assigned according to the location of the injury by the vertebra of the spinal column closest to the injury on the spinal cord.

Cervical (neck) injuries usually result in full or partial tetraplegia (Quadriplegia). However, depending on the specific location and severity of trauma, limited function may be retained.

Continued here:
Spinal cord injury - Wikipedia, the free encyclopedia

SAN DIEGO. (Ivanhoe Newswire) -- According to the Christopher and Dana Reeve Foundation, nearly one in 50 people is living with paralysis. Until now, there wasn't much hope. But a new study involving stem cells has doctors and patients excited.

Two years ago, Brenda Guerra's life changed forever.

Guerra told Ivanhoe, They told me that I went into a ditch and was ejected out of the vehicle.

The accident left the 26-year-old paralyzed from the waist down, and confined to a wheelchair.

I don't feel any of my lower body at all she said.

Guerra has traveled from Kansas to UC San Diego to be the first patient to participate in a ground-breaking safety trial, testing stem cells for paralysis.

Joseph D. Ciacci, MD, Professor of Neurosurgery at UC San Diego told Ivanhoe, We are directly injecting the stem cells into the spine.

The stem cells come from fetal spinal cords. The idea is when they're transplanted they will develop into new neurons and bridge the gap created by the injury by replacing severed or lost nerve connections. They did that in animals and doctors are hoping for similar results in humans. The ultimate goal is to help people like Brenda walk again.

The ability to walk is obviously a big deal not only in quality of life issues, but it also affects your survival long-term Dr. Ciacci said.

Guerra received her injection and will be followed for five long years. She knows it's only a safety trial but she's hoping for the best

More:
Stem Cells for Paralysis: First of Its Kind Study

According to the Christopher and Dana Reeve Foundation, nearly one in 50 people are living with paralysis.

Until now, there wasn't much hope.

But, a new study involving stem cells has doctors and patients excited.

Two years ago, Brenda Guerra's life changed forever.

"They told me that I went into a ditch and was ejected out of the vehicle," says Brenda.

The accident left the 26-year-old paralyzed from the waist down and confined to a wheelchair.

"I don't feel any of my lower body at all," says Brenda.

Brenda has traveled from Kansas to UC San Diego to be the first patient to participate in a ground-breaking safety trial, testing stem cells for paralysis.

"We are directly injecting the stem cells into the spine," says Dr. Joseph Ciacci, a neurosurgeon at UC San Diego.

The stem cells come from fetal spinal cords. The idea is when they're transplanted they will develop into new neurons and bridge the gap created by the injury by replacing severed or lost nerve connections. They did that in animals and doctors are hoping for similar results in humans. The ultimate goal: to help people like Brenda walk again.

Read more:
Stem cell procedures for paralysis patients

Damage to neural tissue is typically permanent and causes lasting disability in patients, but a new approach has recently been discovered that holds incredible potential to reconstruct neural tissue at high resolution in three dimensions. Research recently published in the Journal of Neural Engineering demonstrated a method for embedding scaffolding of patterned nanofibers within three-dimensional (3D) hydrogel structures, and it was shown that neurite outgrowth from neurons in the hydrogel followed the nanofiber scaffolding by tracking directly along the nanofibers, particularly when the nanofibers were coated with a type of cell adhesion molecule called laminin. It was also shown that the coated nanofibers significantly enhanced the length of growing neurites, and that the type of hydrogel could significantly affect the extent to which the neurites tracked the nanofibers.

"Neural stem cells hold incredible potential for restoring damaged cells in the nervous system, and 3D reconstruction of neural tissue is essential for replicating the complex anatomical structure and function of the brain and spinal cord," said Dr. McMurtrey, author of the study and director of the research institute that led this work. "So it was thought that the combination of induced neuronal cells with micropatterned biomaterials might enable unique advantages in 3D cultures, and this research showed that not only can neuronal cells be cultured in 3D conformations, but the direction and pattern of neurite outgrowth can be guided and controlled using relatively simple combinations of structural cues and biochemical signaling factors."

The next step will be replicating more complex structures using a patient's own induced stem cells to reconstruct damaged or diseased sites in the nervous system. These 3D reconstructions can then be used to implant into the damaged areas of neural tissue to help reconstruct specific neuroanatomical structures and integrate with the proper neural circuitry in order to restore function. Successful restoration of function would require training of the new neural circuitry over time, but by selecting the proper neurons and forming them into native architecture, implanted neural stem cells would have a much higher chance of providing successful outcomes. The scaffolding and hydrogel materials are biocompatible and biodegradable, and the hydrogels can also help to maintain the microstructure of implanted cells and prevent them from washing away in the cerebrospinal fluid that surrounds the brain and spinal cord.

McMurtrey also noted that by making these site-specific reconstructions of neural tissue, not only can neural architecture be rebuilt, but researchers can also make models for studying disease mechanisms and developmental processes just by using skin cells that are induced into pluripotent stem cells and into neurons from patients with a variety of diseases and conditions. "The 3D constructs enable a realistic replication of the innate cellular environment and also enable study of diseased human neurons without needing to biopsy neurons from affected patients and without needing to make animal models that can fail to replicate the full array of features seen in humans," said McMurtrey.

The ability to engineer neural tissue from stem cells and biomaterials holds great potential for regenerative medicine. The combination of stem cells, functionalized hydrogel architecture, and patterned and functionalized nanofiber scaffolding enables the formation of unique 3D tissue constructs, and these engineered constructs offer important applications in brain and spinal cord tissue that has been damaged by trauma, stroke, or degeneration. In particular, this work may one day help in the restoration of functional neuroanatomical pathways and structures at sites of spinal cord injury, traumatic brain injury, tumor resection, stroke, or neurodegenerative diseases of Parkinson's, Huntington's, Alzheimer's, or amyotrophic lateral sclerosis.

###

The work was carried out at the University of Oxford and the Institute of Neural Regeneration & Tissue Engineering, a non-profit charitable research organization.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

See the article here:
3-D neural structure guided with biocompatible nanofiber scaffolds and hydrogels

GERMANTOWN, Md., March 16, 2015 /PRNewswire/ -- Neuralstem, Inc. (NYSE MKT: CUR) (the "Company" or "Neuralstem") today reported its financial results for the fourth quarter and year ended December 31, 2014.

"Neuralstem has progressed into a clinical development stage company focused on the central nervous system (CNS)," said Richard Garr, Neuralstem President and CEO. "During 2014 we added two established industry leaders as Independent Directors, Catherine Angell Sohn, Pharm.D. and Sandford Drexel Smith. Dr. Sohn is the former Senior Vice President of Business Development and Strategic Alliance, GSK Consumer Healthcare, at GlaxoSmithKline. Mr. Smith is the former Executive Vice President of Genzyme Corporation. The Company moved forward two lead clinical assets: our small molecule neurogenic drug candidate NSI-189 and our spinal derived neural stem cell therapeutic candidate NSI-566. We established and/or grew clinical research programs with leading investigators at Emory University, University of California, San Diego (UCSD), University of Michigan and Massachusetts General Hospital. Our investigators published and presented proof of principle data in both lead assets as highlighted below. In 2015, we plan to begin clinical development of our NSI-189 small molecule drug in a second indication for the treatment of cognitive deficit from schizophrenia, and we plan to initiate a Phase II clinical trial for the ongoing development program for the treatment of major depressive disorder (MDD). The cell therapy programs in amyotrophic lateral sclerosis (ALS), chronic spinal cord injury (cSCI) and stroke will also move forward. We expect this to be another important year continuing our development and progress across both platforms."

2014 Clinical Program and Business Highlights

Neurogenic Small Molecule Platform Clinical Development

Cell Therapy Platform Clinical Development

NSI-566 spinal cord-derived stem cell therapy under development for the treatment of ALS

NSI-566 spinal cord-derived cell therapy under development for the treatment of cSCI

NSI-566 spinal cord derived stem cell therapy under development for the treatment of motor deficits in stroke

NSI-532.IGF second generation gene engineered cell therapy

2014 Business Highlights

Continued here:
Neuralstem Reports Fiscal 2014 Fourth Quarter Financial And Year-End Business Results

GERMANTOWN, MD, March 12, 2015 -- Neuralstem, Inc. (NYSE MKT: CUR) announced top line data from the Phase II trial of NSI-566 spinal cord-derived neural stem cells under development for the treatment of amyotrophic lateral sclerosis (ALS). The study met primary safety endpoints. The maximum tolerated dose of 16 million transplanted cells and the surgery was well tolerated.

Secondary efficacy endpoints at nine months post-surgery indicate a 47% response rate to the stem cell treatment, as measured by either near-zero slope of decline or positive slope of ALSFRS score in seven out of 15 patients and by either a near-zero decline, or positive strengthening, of grip strength in seven out of 15 patients. Grip strength is an indicator of direct muscle strength of the lower arm. ALSFRS is a standard clinical test used to evaluate the functional status of ALS patients. The average ALSFRS score for responders at 9 months after treatment was 37. Non-responders scored an average of 14. These scores represent 93%, versus 35%, of the baseline score retained, respectively, by the responders versus non-responders at 9 months, which is a statistically significant difference. As measured by an average slope of decline of ALSFRS, responders' disease progression was -0.007 point per day, while non-responders' disease progression was -0.1 per day, which was again statistically significant. Lung function as measured by Seated Vital Capacity shows that responder patients remained within 94% of their starting scores, versus 71% for non-responder patients. The trial met its primary safety endpoints. Both the surgery and cells were well-tolerated, with one patient experiencing a surgical serious adverse event.

"In this study, cervical intervention was both safe and well-tolerated with up to 8 million cells in 20 bilateral injections," said Karl Johe, PhD, Neuralstem Chief Scientific Officer. "The study also demonstrated biological activity of the cells and stabilization of disease progression in a subset of patients. As in the first trial, there were both responders and non-responders within the same cohort, from patients whose general pre-surgical presentation is fairly similar. However, we believe that through the individual muscle group measurements, we may now be able to differentiate the responders from the non-responders.

"Our therapy involves transplanting NSI-566 cells directly into specific segments of the cord where the cells integrate into the host motor neurons. The cells surround, protect and nurture the patient's remaining motor neurons in those various cord segments. The approximate strength of those remaining motor neuron pools can be measured indirectly through muscle testing of the appropriate areas, such as in the grip strength tests. We believe these types of endpoints, measuring muscle strength, will allow us to effectively predict patients that will respond to treatment, adding a sensitive measure of the therapeutic effects after treatment. Testing this hypothesis will be one of the primary goals of our next trial." The full data is being compiled into a manuscript for publication.

"We believe the top-line data are encouraging," said Eva Feldman MD, PhD, Director of the A. Alfred Taubman Medical Research Institute and Director of Research of the ALS Clinic at the University of Michigan Health System, and an unpaid consultant to Neuralstem. "We were able to dose up to 16 million cells in 40 injections, which we believe to be the maximum tolerated dose. As in the first trial, the top-line data show disease stabilization in a subgroup of patients. Perhaps equally as important, we believe the top-line data may support a method of differentiating responders from non-responders, which we believe will support our efforts as we move into the next, larger controlled trial expected to begin this summer."

"The top-line data look very positive and encouraging. If this proportion of patients doing well after treatment can be corroborated in future therapeutic trials, it will be better than any response seen in any previous ALS trials," said site principal investigator, Jonathan D. Glass, MD, Director of the Emory ALS Center. "Elucidating which factors define a patient who may have a therapeutic response to the stem cell treatment will be the next key challenge. We are hopeful that a set of predictive algorithms can be established to help pre-select the responders in our future trials."

"We were very excited to participate as a site in this clinical trial," said Merit Cudkowicz, MD, Chief of Neurology, Massachusetts General Hospital and Co-Chair of the Northeast ALS Consortium (NEALS). "We are hopeful with respect to the top-line results and we need to move swiftly and safely forward to confirm the responder effect and identify people who might benefit from this treatment approach."

The open-label, dose-escalating trial treated 15 ambulatory patients, divided into 5 dosing cohorts, at three centers, Emory University Hospital in Atlanta, Georgia, the ALS Clinic at the University of Michigan Health System, in Ann Arbor, Michigan, and Massachusetts General Hospital in Boston, Massachusetts, and under the direction of principal investigator (PI), Eva Feldman, MD, PhD, Director of the A. Alfred Taubman Medical Research Institute and Director of Research of the ALS Clinic at the University of Michigan Health System. Dosing increased from 1 million to 8 million cells in the cervical region of the spinal cord. The final trial cohort also received an additional 8 million cells in the lumbar region of the spinal cord.

The company anticipates commencing a later-stage, multicenter trial of NSI-566 for treatment of ALS in 2015. Neuralstem has received orphan designation by the FDA for NSI-566 in ALS.

###

Excerpt from:
Neuralstem announces topline results of Phase II ALS trial

Pioneering treatment has allowed wheelchair-bound patients to run again Patient given high dose of chemotherapy to wipe out faulty immune system Therapy then uses person's own stem cells to fight the devastating disease It may be the first ever treatment tosuccessfullyreverse symptoms of MS

By Fiona Macrae for the Daily Mail

Published: 13:27 EST, 1 March 2015 | Updated: 02:54 EST, 2 March 2015

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Britons left wheelchair-bound by multiple sclerosis can walk, run and even dance again after being given a pioneering stem cell treatment.

Doctors have described the recoveries as miraculous, while patients say they have been given their lives back.

The treatment uses a patients own stem cells the bodys master cells to fight the disease.

Recovery: MS sufferer Holly Drewerybecame wheelchair-bound after the birth of daughter Isla, but thanks tothe stem cell transplant shecan dance, run and chase after Isla in the park

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MS stem cell treatment hailed 'miraculous' as patients make dramatic recovery

A new stem-cell treatment that reboots the entire immune system is enabling multiple sclerosis sufferers to walk, run and even dance again, in results branded "miraculous" by doctors.

Patients who have been wheelchair-bound for 10 years have regained the use of their legs in the ground-breaking therapy, while others who were blind can now see again. The treatment is the first to reverse the symptoms of MS, which is incurable, and affects about 100,000 people in Britain.

The two dozen patients who are taking part in the trials at the Royal Hallamshire Hospital, Sheffield, and Kings College Hospital, London, have effectively had their immune systems "rebooted". Although it is unclear what causes MS, some doctors believe it is the immune system itself that attacks the brain and spinal cord, leading to inflammation pain, disability and, in severe cases, death.

In the new treatment, specialists use a high dose of chemotherapy to knock out the immune system before rebuilding it with stem cells taken from the patient's own blood.

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"Since we started treating patients three years ago, some of the results we have seen have been miraculous," Prof Basil Sharrack, a consultant neurologist at Sheffield Teaching Hospitals NHS Foundation Trust, said.

"This is not a word I would use lightly, but we have seen profound neurological improvements."

Holly Drewry, 25, of Sheffield, was wheelchair bound after the birth of her daughter, Isla, two years ago. She claims the new treatment has transformed her life.

"It worked wonders," she said. "I remember being in the hospital ... after three weeks, I called my mum and said: 'I can stand'. We were all crying. I can run a little bit, I can dance. I love dancing, it is silly but I do."

However, specialists warn that patients need to be fit to benefit from the new treatment.

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'Miraculous' stem-cell treatment reverses symptoms of multiple sclerosis

By Ashley Dunkak @AshleyDunkak

CBS DETROIT Murray Howe, the head of the radiology department at ProMedica Toledo Hospital, understands the skepticism of those who question the stem cell treatment his father Gordie, also known as Mr. Hockey, received in December in Tijuana, Mexico.

Gordies health had been slowly declining even before the stroke he suffered in late October, and he was essentially bedridden when Murray and his brother Marty took him to Mexico to participate in a clinical trial. They did not have high hopes he was so far gone, Murray recalled but after each step of the two-part process, Gordie improved rapidly, once again able to walk and talk, repossessed of his wit and humor. Murray and his siblings were floored. So were the therapists who had been working with Gordie after his stroke.

Some physicians have scoffed at the idea of stem cells helping an individual who has had a stroke, but Murray a doctor himself says his fathers recovery after treatment opened his eyes to stem cells as a potential game-changer.

Speaking as a medical professional, its so frustrating when you cant really do anything for a patient, said Howe, the head of the radiology department at Toledo Hospital. You give them kind of a death sentence and you say, Well thats all you get. Theres nothing we can really offer. Its so sad. So now to be able to have on the brink of some huge hope for these patients is really, really exciting. As a medical professional, to me, theres never been anything more exciting in my entire career than this.

Murray does not blame people for being skeptical, and he agrees more research on the capabilities of stem cells is needed to show definitively what they can do. To say Murray is optimistic, however, would be a serious understatement.

Theres quite a few individuals out there who are calling themselves stem cell experts or this or that, kind of saying that theres no data to support that stem cells work on ischemic strokes, but thats really not true at all, Murray said. Theres at least 50 clinical studies that are going on across the world that are demonstrating its safety and working on demonstrating its efficacy, and the preliminary results on the ones that Ive seen are tremendous, so the data is clearly there. I think that people across the world in the next couple years are going to be as blown away as I was with our father when they see the power of stem cells and what they do for patients with not just stroke but with dementia and traumatic brain injuries and spinal cord injuries.

My dads case is by no means the only one, Murray continued. Hes kind of like in the middle. Theres examples of patients that have had a far greater result. Im so thrilled for my dad, but by no means was my dad a fluke or a random event. The studies are ongoing, and I think the point of any of the, I guess, naysayers is that Gordie Howe may be anecdotal and we need more research, and I totally agree with that. In fact, based on what weve seen with my father, I would say that we as a country and as a world should make a concerted effort to put as much time and energy as we can into investigating the power of stem cells because I really think that based on what Im seeing this is going to be a game-changer for medicine and a game-changer for quality of life for so many people that have non-option diseases like stroke or dementia.

Heading to Tijuana for treatment was a last-ditch effort to save Gordie, but it was not one the family undertook on a whim, Murray said.

Im well aware of hucksters and con games and this type of thing, and our family has never been about traveling the world to find the miracle cure, Murray said. Im a very mainstream physician. Ive always relied heavily on data and on long-term studies to prove the safety and efficacy of any treatment. For our father, we just our goal has always just been quality of life and comfort. When my mom was sick with her dementia that was our only priority was just keep her comfortable, keep her healthy, as healthy as possible, and keep her safe, and that was it. We had a number of people contact us saying, You know, we could help your mom with this pill and that pill, and I looked at everything that anybody presented to us, but to me there was nothing that showed any data that would made me want to experiment, if you will, with my mom.

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Gordie Howes Son Says Dads Recovery No Fluke, Excited For Future Of Stem Cell Treatment

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Treatment for the crippling condition is currently limited to basic pain relief or complex joint replacement surgery.

But trials using stem cells have shown astonishing results with tissue almost as good as new after just three months.

Professor Sue Kimber, who led the research, said: This work represents an important step forward in treating cartilage damage using embryonic stem cells to form new tissue.

It may offer a new line of therapy for people with crippling joint pain and we now need this process to be developed for patients.

Osteoarthritis occurs when cartilage at the ends of bones wears away causing severe pain and stiffness.

Researchers say the latest experiments show the procedure could potentially be a safe and effective treatment for more than eight million people who suffer from jointdamage and inflammation.

In the experiments, led by teams at Manchester University and Arthritis Research UK, discarded embryonic stem cells from IVF clinics were transformed into cartilage cells.

These were transplanted into rats with defective joints.

Tests showed the high-quality artificially grown tissue quickly aided the repair of the joint.

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Arthritis cure is on the way: Scientists make new breakthrough using embryonic stem cells