말초신경의 재생에 관한 논문. 반드시 정리해야

[문형철]

말초신경은 놀랍게 재생한다.

목디스크, 허리디스크, 수근관 증후군, 이상근 증후군, 족근관 증후군, 각종 말초신경질환에서 말초신경은 손상된다.

신경은 어떻게 재생하고 어떻게 퇴행되는가?

이 분야에 대한 분자생물학적 기전까지 이해해봐야겠다.

말초신경의 재생.pdf

SUMMARY

The peripheral nervous system has astonishing regenerative capabilities in that cut nerves are able to reconnect and re-establish their function. Schwann cells are important players in this process, during which they dedifferentiate to a progenitor/ stem cell and promote axonal regrowth. 

- 말초신경계는 놀라운 재생능력을 가지고 있어 원래기능을 회복하는 능력을 가짐

- 쉬반 세포는 말초신경 재생과정에서 가장 중요한 세포. 특히 axonal regrowth!

Here, we report that fibroblasts also play a key role. Upon nerve cut, ephrin-B/EphB2 signaling between fibroblasts and Schwann cells results in cell sorting, followed by directional collective cell migration of Schwann cells out of the nerve stumps to guide regrowing axons across the wound. Mechanistically, we find that cell-sorting downstream of EphB2 is mediated by the stemness factor Sox2 through N-cadherin relocalization to Schwann cell-cell contacts.

- 여기서 우리는 섬유아세포가 말초신경재생에 중요한 역할을 수행한다고 보고함. 

- 신경을 자르는 실험에서  ephrin-B/EphB2 신호는 섬유아세포와 슈반 세포사이에서 cell sorting을 야기하고, 이어서 치유를 넘어서 축삭재생과 신경재생을 야기함. 

In vivo, loss of EphB2 signaling impaired organized migration of Schwann cells, resulting in misdirected axonal regrowth. Our results identify a link between Ephs and Sox proteins, providing a mechanism by which progenitor cells can translate environmental cues to orchestrate the formation of new tissue.

The peripheral nervous system (PNS) differs from the central nervous system (CNS) in that it is capable of remarkable regeneration even after severe injury. After an injury, both PNS and CNS axons distal to the lesion degenerate, but only PNS axons regrow and reconnect to their targets (Navarro, 2009; Zochodne, 2008). The distinct ability of peripheral nerves to regrow back to their targets hinges on the regenerative properties of its glia, the Schwann cells. Adult peripheral nerves lack a stem cell population to produce new glia. Instead, mature differentiated Schwann cells retain a high degree of plasticity throughout adult life and upon injury shed their myelin sheaths and dedifferentiate en masse to a progenitor/stem cell-like state (Kruger et al., 2002; Scherer and Salzer, 2001). 

Dedifferentiated Schwann cells are key to nerve repair for two main reasons. First, they can replenish lost or damaged tissue by proliferating. Second, they produce a favorable environment for axonal regrowth both by helping to clear myelin debris and by forming cellular conduits or corridors, known as bands of Buengner, that guide axons through the degenerated nerve stump and back to their targets (Zochodne, 2008).

Regeneration is particularly successful after crush injuries, because the basal lamina surrounding the axon/Schwann cell nerve unit is maintained, preserving the integrity of the original axonal paths and allowing highly efficient and accurate reinnervation

(Nguyen et al., 2002). Regeneration also occurs after more severe injuries that significantly disrupt nerve structure, such as complete transection. 

However, the process is less efficient as transection presents several additional hurdles for successful repair (Nguyen et al., 2002). Upon cut, nerve stumps on either side of the cut retract, generating a gap, which must be bridged by new tissue; moreover, the regrowing axons from the proximal stump must travel through this newly formed tissue (referred to as the ‘‘nerve bridge’’) to reach the distal stump and ultimately their target organs (McDonald et al., 2006; Zochodne, 2008). While many studies have contributed to our understanding of how peripheral nerves repair after crush injuries, much less is understood about nerve regeneration after full transection. 

In particular, little is known about the mechanisms that control the formation and organization of new nerve tissue or how regrowing axons successfully negotiate the nerve bridge to rejoin the distal stump. Dissecting these events is key not only to the development of therapeutic strategies for the improvement of nerve regeneration but also to the understanding of basic principles governing the biology of stem cells and tissue development.

Ephrin/Ephs are a large family of receptor tyrosine kinases that function to convey positional information to cells (Lackmann and Boyd, 2008; Pasquale, 2008). During development, they direct cell migration, regulate tissue patterning, and help form tissue boundaries. In adulthood, they participate in the control of tissue homeostasis and, when aberrantly expressed, can contribute to cancer development and progression. Eph receptors are subdivided into two classes: type A, which preferentially bind GPI-anchored ephrin-A ligands, and type B, which bind transmembrane B-type ephrins, although crosstalk between the two classes has been reported (Pasquale, 2008). Interaction

between ephrin ligands and Eph receptors triggers complex

bidirectional signaling, which modulates cell adhesion and repulsion,

largely by reorganizing the actin cytoskeleton. A great deal

is known about how ephrin/Eph signaling controls actin

dynamics to cause rapid cell responses such as movement

(Arvanitis and Davy, 2008). In contrast, very little is known about

whether ephrin/Eph signaling can cause permanent changes in

cell behavior by regulating gene expression‎, in spite of the

potential importance of such mechanisms in development and

regeneration.

[고인성]

http://www.sports.re.kr/common/download.jsp?filePath=magazine/5094920100701095030.pdf&fileName=5094920100701095030.pdf