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Induced pluripotent stem cells (iPSCs), with both pluripotency and replication competence similar to embryonic stem cells (ESCs), have been developed from mouse fibroblasts in 2006 by Yamanaka et al. iPSCs are unique in employing somatic cells for their production, and can avoid ethical issues existing in ESCs. It is clear that progress in technology to produce iPSCs is one of the most crucial achievements of medicine in this century. Technology with the new pluripotent cells will offer many advantages in the field of regeneration medicine supplying new tissues to the injured organ and/or development of methodology to uncover many genetic diseases. On the other hand, we have to await adequate progress in issues regarding iPSCs, including enhanced efficiency to obtain iPSCs, the technology to produce organs from the cells, avoidance of tumorigenesis and decrease in immunity in response to iPSCs.

The central nervous system (CNS) injury causes severe loss of functions, and the development of therapies to recover the functions can be an important target. The present study highlighted the preservation-oriented therapy by transferring genes to the injured neurons. To identify therapeutic targets for the preservative therapies of injured CNS, we focused on clarifying the mechanism underlying the degeneration and regeneration of neurons after injuries using nerve injury models of animals. We have identified several genes, some of which were the survive-promoting and others were death-promoting molecules. In addition another subset of genes were assumed to be associated with promoting nerve regeneration. The single expression of variety of molecules by a viral vector was proved to have the potential to rescue and recover, and this was also confirmed in CNS injury model. We assumed that the most important issue was the balance of levels between the pro-survive and pro-death molecules, which expressed in response to nerve injury. Those suggest that variety of molecules could be a therapeutic target for neurodegenerative disease as well as the neuron protection after traumatic injury. Combining both the transplantation-oriented and the preservation-oriented strategies would give us more potent therapeutic possibilities.

Interleukin-6 (IL-6) has been demonstrated to play a pivotal role in CNS trauma as a proinflammatory cytokine which regulates inflammatory response. Not only being a mediator of inflammation, but IL-6 induces neural stem/progenitor cells to undergo astrocytic differentiation selectively in the injured CNS. These effects are considered to coordinate to prevent the CNS repair after traumatic injury. Consistently, we previously reported that the administration of anti-IL-6 receptor antibody (MR16-1) immediately after spinal cord injury in mice decreased the number of invading inflammatory cells and the severity of connective tissue scar formation, and led to improved functional recovery. These findings suggest that neutralization of IL-6 signaling in the acute phase of SCI will be beneficial for CNS repair. A critical merit of this anti-IL-6 receptor antibody is that humanized antibody to human IL-6 receptor (MRA; Atlizumab) has already been reshaped. However, there are several studies which show beneficial aspects of IL-6 signaling in the pathology of CNS trauma. Further investigation of the mechanisms how MR16-1 reduces tissue damage should be required for clinical application.

Spontaneous regeneration of lesioned fibers is limited in the adult central nervous system due to an unfavorable environment. Several myelin-derived proteins have been identified to inhibit neurite outgrowth in vitro. These proteins induce activation of Rho in some neurons. Inhibition of Rho or Rho-kinase, downstream effector of Rho, promotes axon regeneration in vivo. Recent reports suggest that several other proteins are axon growth inhibitors. Therapeutic strategy to block the multiple axon growth inhibitors may provide efficient tools that produce functional regeneration following injuries to the central nervous system. In addition, it is noted that synaptic plasticity in pre-existing pathways and the formation of new circuits through collateral sprouting of lesioned and unlesioned fibers are important components of the recovery process.

Endothelins and their receptor of type B (ETBR) that couples with G-protein are widely distributed in the mammalian central nervous system (CNS). ETBR mainly exists on astrocytes, and endothelins exert mitogenic action on astrocytes through stimulation of the receptor. The intracellular signaling of ETBR in astrocytes is converged in the activation of mitogen-activated protein kinase through a protein kinase C-dependent pathway and a pertussis toxin-sensitive G-protein-mediated pathway. We demonstrated that cultured astrocytes. When differentiated and growth-arrested by treatment with dibutyryl cyclic AMP, abundantly expressed ETBR and these cells immediately entered into a proliferative state in response to endothelin-1 at the plasma level. This has the following physiological implication in vivo: plasma-derived endothelin-1 intrudes into parenchyme upon CNS damage, and it initiates astrogliosis through activation of ETBR. We used two models of CNS injury in rats. The first is a brain edema model induced by cold-injury, and the second is a spinal cord injury model, both of which allow plasma to exude into the injured tissues and subsequently trigger sequential proliferative responses of astrocytes after the injury. Anti-endothelin monoclonal antibody and SB209670, an endothelin receptor antagonist, specifically and potently inhibited astrocytic proliferation 24 hr after the injury. It is concluded that endothelin-1 plays a key role for initiation of astrocytic proliferation in the acute phase of CNS damage.