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

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

Points regarding cell transplantation for the treatment of spinal cord injury

Transplantation of somatic cells, including bone marrow stromal cells (BMSCs), bone marrow mononuclear cells (BMNCs), and choroid plexus epithelial cells (CPECs), enhances the outgrowth of regenerating axons and promotes locomotor improvements. They are not integrated into the host spinal cord, but disappear within 2-3 weeks after transplantation. Regenerating axons extend at the spinal cord lesion through the astrocyte-devoid area that is filled with connective tissue matrices. Regenerating axons have characteristics of peripheral nerves: they are associated with Schwann cells, and embedded in connective tissue matrices. It has been suggested that neurotrophic factors secreted from BMSCs and CPECs promote “intrinsic” ability of the spinal cord to regenerate. Transplanted Schwann cells survive long-term, and are integrated into the host spinal cord, serving as an effective scaffold for the outgrowth of regenerating axons in the spinal cord. The disadvantage that axons are blocked to extend through the glial scar at the border of the lesion is overcome. Schwann cells have been approved for clinical applications. Neural stem/progenitor cells (NSPCs) survive long-term, proliferate, and differentiate into glial cells and/or neurons after transplantation. No method is available at present to manipulate and control the behaviors of NPSCs to allow them to appropriately integrate into the host spinal cord. NPSP transplantation is not necessarily effective for locomotor improvement

Cell transplantation for the treatment of spinal cord injury - bone marrow stromal cells and choroid plexus epithelial cells

Transplantation of bone marrow stromal cells (BMSCs) enhanced the outgrowth of regenerating axons and promoted locomotor improvements of rats with spinal cord injury (SCI). BMSCs did not survive long-term, disappearing from the spinal cord within 2-3 weeks after transplantation. Astrocyte-devoid areas, in which no astrocytes or oligodendrocytes were found, formed at the epicenter of the lesion. It was remarkable that numerous regenerating axons extended through such astrocyte-devoid areas. Regenerating axons were associated with Schwann cells embedded in extracellular matrices. Transplantation of choroid plexus epithelial cells (CPECs) also enhanced axonal regeneration and locomotor improvements in rats with SCI. Although CPECs disappeared from the spinal cord shortly after transplantation, an extensive outgrowth of regenerating axons occurred through astrocyte-devoid areas, as in the case of BMSC transplantation. These findings suggest that BMSCs and CPECs secret neurotrophic factors that promote tissue repair of the spinal cord, including axonal regeneration and reduced cavity formation. This means that transplantation of BMSCs and CPECs promotes "intrinsic" ability of the spinal cord to regenerate. The treatment to stimulate the intrinsic regeneration ability of the spinal cord is the safest method of clinical application for SCI. It should be emphasized that the generally anticipated long-term survival, proliferation and differentiation of transplanted cells are not necessarily desirable from the clinical point of view of safety

Regional differences of relationships between atrophy and glucose metabolism of cerebral cortex in patients with Alzheimer\u27s disease

8th Congress of the World Federation of Nuclear Medicine & Biolog