Patterns of outgrowth of regenerating axons through spinal cord lesion

We found that bone marrow stromal cells (BMSCs) do not survive for long enough to serve as a scaffold for regenerating axons after transplantation in the injured spinal cord of rats. However, axonal regeneration was facilitated, possibly by trophic factors secreted from transplanted BMSCs. Regenerating axons were not associated with astrocytes, but surrounded by Schwann cells (SCs), and embedded in collagen fibril matrices just as the axons of peripheral nerves. Experiments involving the transplantation of SCs themselves indicated that, besides exogenous SCs, intrinsic SCs infiltrated the lesion and formed myelin sheaths on regenerating axons in the same manner as described with BMSC transplantation. The transplantation of olfactory ensheathing cells (OECs) showed that OECs themselves enclosed regenerating axons in the same manner as SCs. No study has been carried out to address whether such Schwann-like cells were derived from transplanted OECs or intrinsic SCs. However, the possibility cannot be excluded that intrinsic SCs contributed to surround regenerating axons. Neural stem cells (NSCs) derived from iPS cells survived long-term, emanating numerous axons that extended over a long distance through the host spinal cord tissue. However, no myelination occurred on regenerating axons, and no behavioral improvement was observed. It would be difficult to manipulate iPS-derived NSCs to appropriately integrate them into the host spinal cord tissue. In this respect, iPS cells have crucial problems concerning whether they can be integrated appropriately into the host tissue. Muse cells (multilineage-differentiating stress-enduring cells) were separated as SSEA3-positive cells from BMSCs. Transplanted Muse cells survived long-term, but they were not as effective as non-Muse cells or BMSCs for the treatment of infarcted brains, suggesting that trophic factors from non-Muse cells and BMSCs are involved in those effects. These findings indicate that intrinsic SCs and trophic factors released from transplants may play important roles in nerve regeneration of the spinal cord. Differing from the generally believed pattern of regeneration, glial cells are not necessarily needed as the scaffolds for growing axons in the spinal cord

Cell transplantation studies on the treatment of spinal cord injury using clinically relevant cells

Many different kinds of cells have been studied for transplantation in experimental animals including rats with spinal cord injury. This short review focused on adult somatic and umbilical cord cells to be used for therapy of spinal cord injury. Adult somatic cells have no inherent ethical problems in using for clinical application. Embryonic stem (ES) cells, neural stem cells, and induced pluripotent stem (iPS) cells were excluded. Bone marrow stromal cells and olfactory ensheathing cells have already been used clinically for transplantation to patients with spinal cord injury. Other cells dealt with in this review include dental pulp-derived, skin-derived, adipose-derived, and umbilical cord-derived stem cells. Muse cells, and choroid plexus epithelial cells

Choroid plexus -with special reference to neuroprotective function-

Choroid plexus (CT) produces the cerebrospinal fluid (CSF) that fills the ventricles and subarachnoidal space, and infiltrates the intercellular spaces of CNS parenchyma. CP transplantation enhances axonal outgrowth in the spinal cord lesion. Cultured choroid plexus epithelial cells (CPECs) secret neurotrophic factors into the medium. CP undergoes cytological changes in diseases such as Alzheimer and Huntingon\u27s disease. The ischemia-injured infraction due to middle cerebral artery occlusion is suppressed by transplantation of CPECs into the CSF in the rat. Allo- or xenotransplantation of encapsulated CP has been studied for the treatment of experimental Huntington\u27s disease. CP can be regarded as the neurotrophic center of the CNS, regulating and maintaining the normal brain function via CSF

Characterization of T lymphocyte phenotype and phosphorylated axonal neurofilament subunit H level associated with presumptive and diagnosed progressive myelomalacia in dogs

The aim of this study was to characterize the T lymphocyte phenotype and phosphorylated axonal neurofilament subunit H (pNF-H) in dogs diagnosed with progressive myelomalacia (PM) and dogs with presumptive PM. A retrospective case series of six dogs with confirmed PM and 8 dogs with presumptive PM was in vesrigared, conducted and clinical signs, magnetic resonance imaging (MRI), the somatosensory evoked potential. and T lymphocyte phenotype in clinical records and pNF-H levels in the peripheral blood were evaluated. pNF-H levels were determined in both study dogs and healthy controls (beagles). PM was clinically diagnosed based on : (Berger et al. 2007) MRI of disc-associated spinal cord compression, (Boylan et al. 2009) clinical progression from initial paraparesis or paraplegia, to thoracic limb lower motor neuron paresis, to tetraplegia associated with cranial migration to the extent of cutaneous trunci reflex loss and analgesia, leading to death via respiratory paralysis, and (Ceron et al. 2005) histological examination. All PM dogs were paraplegic and had signs of lower motor neuron lesions. The CD4+/CD8+ ratio in 13 out of the 14 dogs (92.9%) was significantly higher than that in healthy controls (p<0.001). pNF-H was only detected in the peripheral blood of PM dogs. In some PM dogs, we did not observe signal hyperintensity on T2-weighted MRI. Our study results indicate that the detection of pNF-H and a high CD4+/CD8+ ratio in the peripheral blood may Facilitate earlier diagnosis of PM than is possible with MRI

Effects of locomotor training on the functional recovery from the spinal cord injury

This mini-review surveys several representative rehabilitation studies using a treadmill or other methods of locomotor exercises in humans and experimental animals with spinal cord injury. The methods and effect of locomotor training employed in individual studies are explained and the importance of the sensory input and body weight loading in the stimulation of the central pattern generator is emphasized. The establishment of neural networks by regenerating and/or spared axons is the basis of locomotor improvement. Although regenerating axons are found within the lesion, it is difficult to demonstrate the development of new neural connections. Muscle activity is another important factor in recovery from spinal cord injury. Robotic trainings of rats on a treadmill is not considered suitable for a rehabilitation study, because the robotic movement of the hind limbs differs from natural quadrupedal walking. Clinically, driven gait orthosis is used effectively for locomotor training of patients with SCI

Adult stem cell transplantation for the treatment of spinal cord injury

Cell transplantation has been extensively studied to treat spinal cord injury (SCI). Various kinds of cell have been used as transplants. The most promising transplants are autografts, in which transplantable cells should be derived from adult tissues. In this respect, bone marrow stromal cells (BMSCs), adipose-derived stem cells (ADSCs), and skin-derived stem cells (SDSCs) are appropriate candidates as transplants for SCI. In fact, BMSCs have been extensively studied as a promising transplant for the treatment of SCI. Several studies have been reported concerning the effects of transplanting ADSCs and SDSCs for SCI. On the other hand, embryo-derived or genetically altered cells are associated with marked ethical and tumorigenic concerns. In the present review, we focus on cell transplants that are easily obtainable from adult tissues, and readily applicable for SCI. We think that only those cells that can be used as transplants for clinical cases have a meaning in regenerative medicine

Degenerative and of regenerative changes in the dorsal funiculus of the cryoinjured spinal cord of rats -electron microscopic study-

The morphological changes were examined in the dorsal funiculus after cryoinjury to the spinal cord at Th10 in the rat. Cryoinjury was performed by contacting a liquid nitrogen-frozen metal rod with the dorsal surface of the spinal cord. The frozen spinal cord was thawed spontaneously. This freeze-thawing treatment was repeated three times. The histological changes were examined by light and electron microscopy from 2 to 60 days after cryoinjury. The present study focused on the electron microscopic findings of the degenerative and regenerative changes of nerve fibers and glial cells following injury. In typical Waller degeneration, myelin sheaths of degenerated axons were separated from oligodendrocytes, and phagocytozed by macrophages. Within the lesion, while glial cells including oligodendrocytes were degraded, some axons were rescued from the damage, surviving as demyelinated axons after the degradation of associated oligodendrocytes. Such demyelinated axons were later remyelinated by oligodendrocytes or Schwann cells. This might be a major factor contributing to the locomotive recovery of the animal. Growth cones were formed even after a long period following cryoinjury at the proximal stump of the injured nerves. This suggests that nerve fibers have a strong ability to regenerate in the spinal cord dorsal funiculus. A cavity was usually formed in the epicenter to rostral part of the lesion. Cavity formation is a critical barrier to spinal cord regeneration. The main strategies for spinal cord regeneration might be to rescue and restore neural tissues from degeneration, and prevent cavity formation by providing a sufficient blood supply to ensure tissue survival and axonal outgrowth

Are the long-term survival, proliferation, and differentiation of transplanted cells desirable in clinical application for spinal cord injury?

Cell transplantation studies of spinal cord injury have a premise that the transplants should be integrated in the host spinal cord tissue, differentiate into neural cells, and re-establish neural circuits, leading to the improvement of locomotor functions. However, the long-term survival, extensive proliferation, and/or differentiation of transplanted cells are not necessarily desirable clinically, and may, on the contrary, cause serious problems regarding the safety of transplants. The excessive proliferation, migration, and/or differentiation of transplanted cells may deteriorate the histological as well as functional organization of the host spinal cord. The present communication will discuss the feasibility of using three kinds of cell as transplants, including bone marrow-derived cells (BMDCs), Schwann cells, and neural stem/progenitor cells (NSPCs). BMDCs enhance tissue recovery and locomotor improvements; however, they disappear within 2-3 weeks after transplantation from the host spinal cord. This indicates that BMDCs do not serve as scaffolds for the growth of regenerating axons, but promote "endogenous" regenerating capacities of the host spinal cord, probably by secreting some trophic factors. This short-term survival of transplants, although appearing to be a disadvantage, guarantees the safety of cell transplantation. The transplantation of BMDCs is now at the Phase I/II stage of clinical application. Schwann cells have been studied extensively as a transplant material for spinal cord injury. Schwann cells survive long-term, and moderately proliferate and/or migrate in the spinal cord. It can be said that Schwann cells become well integrated in the host spinal cord. Therefore, they are regarded as a safe transplant. NSPCs proliferate, migrate, and differentiate extensively after transplantation in the host spinal cord. It is impossible at present to manipulate or control the proliferation/migration/differentiation of NPSCs to make them properly integrate in the host spinal cord. NSPCs are not considered safe for clinical application. BMDCs and Schwann cells are clinically relevant, while NS/PCs are clinically irrelevant