Fasting Differentially Modulates the Immunological System: Its Mechanism and Sex Difference

The immunological properties and hormonal metabolism in rodents are affected by physical and psychological stress more strongly in males than in females. To elucidate the mechanism and physiological significance of the sex difference in the susceptibility of animal to stresses, changes in the immunological system in plasma and intestine and hormonal status in plasma were compared among 8-week-old male and female ICR mice before and after fasting. During the fasting of animals, the expression of immunoglobulin A in intestinal mucosa, and cortisol, interleukin-10 and interferon-γ in plasma increased. These changes occurred more apparently in males than in females. Under identical conditions, the plasma levels of testosterone decreased markedly with concomitant occurrence of apoptosis in the testis, while the plasma levels of estradiol decreased calmly, and no appreciable apoptosis occurred in the ovary. These results indicate that testosterone enhances the stress-induced modulation of the immune system by some mechanism that was antagonized by estradiol

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

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

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

Effects of bone marrow stromal cell transplantation through CSF on the subacute and chronic spinal cord injury in rats.

It has been demonstrated that the infusion of bone marrow stromal cells (BMSCs) through the cerebrospinal fluid (CSF) has beneficial effects on acute spinal cord injury (SCI) in rats. The present study examined whether BMSC infusion into the CSF is effective for subacute (1- and 2-week post-injury), and/or chronic (4-week post-injury) SCI in rats. The spinal cord was contused by dropping a weight at the thoracic 8-9 levels. BMSCs cultured from GFP-transgenic rats of the same strain were injected three times (once weekly) into the CSF through the fourth ventricle, beginning at 1, 2 and 4 weeks post-injury. At 4 weeks after initial injection, the average BBB score for locomotor assessment increased from 1.0-3.5 points before injection to 9.0-10.9 points in the BMSC-injection subgroups, while, in the PBS (vehicle)-injection subgroups, it increased only from 0.5-4.0 points before injection to 3.0-5.1 points. Numerous axons associated with Schwann cells extended longitudinally through the connective tissue matrices in the astrocyte-devoid lesion without being blocked at either the rostral or the caudal borders in the BMSC-injection subgroups. A small number of BMSCs were found to survive within the spinal cord lesion in SCI of the 1-week post-injury at 2 days of injection, but none at 7 days. No BMSCs were found in the spinal cord lesion at 2 days or at 7 days in the SCI of the 2-week and the 4-week post-injury groups. In an in vitro experiment, BMSC-injected CSF promoted the survival and the neurite extension of cultured neurons more effectively than did the PBS-injected CSF. These results indicate that BMSCs had beneficial effects on locomotor improvement as well as on axonal regeneration in both subacute and chronic SCI rats, and the results also suggest that BMSCs might function as neurotrophic sources via the CSF

Experimental designs.

<p>The figure shows the three experimental groups of cell injection. BMSCs in PBS were injected into the CSF three times (once weekly) into the 4th ventricle 1, 2, or 4 weeks after contusion injury to the spinal cord. For the control, the vehicle (PBS) without BMSCs was injected in the same manner. Cell- or vehicle-injection started at 1 week post-injury (PI) in Group 1 (A), at 2 weeks PI in Group 2 (B), and at 4 weeks PI in Group 3 (C). Most rats were fixed at 4 weeks following the initial injection. A few rats were fixed 2 weeks after the initial injection.</p