Research Article: Reactive Astrocytes in Glial Scar Attract Olfactory Ensheathing Cells Migration by Secreted TNF-α in Spinal Cord Lesion of Rat

Date Published: December 3, 2009

Publisher: Public Library of Science

Author(s): Zhida Su, Yimin Yuan, Jingjing Chen, Li Cao, Yanling Zhu, Liang Gao, Yang Qiu, Cheng He, Xiao-Jiang Li.

Abstract: After spinal cord injury (SCI), the formation of glial scar contributes to the failure of injured adult axons to regenerate past the lesion. Increasing evidence indicates that olfactory ensheathing cells (OECs) implanted into spinal cord are found to migrate into the lesion site and induce axons regeneration beyond glial scar and resumption of functions. However, little is known about the mechanisms of OECs migrating from injection site to glial scar/lesion site.

Partial Text: Damage to adult mammalian central nervous system (CNS) leads to persistent functional deficits for the lack of axonal regeneration and reconnection with correct synaptic targets. The failure of spontaneous anatomical and functional repair is due not merely to the intrinsic incapacity of the neuron to regenerate but rather to the presence of a hostile environment in the lesion site. As the major cell type in CNS, astrocytes provide a variety of critical supportive functions that maintain neuronal homeostasis. When the CNS is damaged, astrocytes undergo an injury response and become reactive, characterized by hyperplasia, hypertrophy and an massive up-regulation of intermediate filament (IF) proteins, and leads eventually to the formation of a dense glial scar network at the lesion site [1]. The glial scar which composed primarily of reactive astrocytes has long been implicated as a major impediment to axon regeneration and functional outcome after SCI and other forms of CNS injury [2], [3]. It constitutes a mechanical obstacle and a biochemical barrier to preventing successful regeneration, as several classes of growth inhibitory molecules are upregulated and have been shown to contribute to the failure of axon regeneration [2], [4], [5], [6]. On the other hand, increasing evidence indicates that glial scar might also possess several important beneficial functions such as stabilizing fragile CNS tissue after injury [7], [8], [9]. After injury, reactive astrocytes form a dense scar tissue that has been suggested to seclude inflammatory cells, demarcate the lesion area, and separate the injured tissue from its surroundings [9]. Astrocytes have an important scavenging activity, which is crucial for regulating excessive levels of glutamate, K+ and other ions [10]. Moreover, the glial scar is reported to fill the gaps in the lesion area, creating a scaffold for the vascularization network [11].

Owing to the lack of axonal regeneration and reconnection with correct synaptic targets, the repair of CNS damage, especially SCI, continues to be a major challenge. Because of the existence of glial scar in damaged CNS, severed axons are difficult to regenerate pass the lesion site. It has been reported that long-distance axonal regeneration beyond the lesion centre in the transected adult spinal cord is induced by transplantation of OECs [20], [38], [39]. OECs transplantation can inhibit hypertrophic response of host astrocyte, reduce CSPG expression in reactive astrocytes, and negatively regulate glial scar formation [21], [40], [41], [42]. Several studies report that OECs induce an increase in the formation of new blood vessels after SCI [20], [43], [44], [45], which may function as a scaffold for migrating glia as well as for regrowing axons [44]. Data from Li et al. [46] demonstrate that OECs actively phagocytose degenerating axons. Recent studies indicate that OECs form a channel- or tube-like structure within the lesion to provide an oriented matrix for axons to grow on or through [15], [17]. It is noteworthy that the migratory properties of OECs are considered to account in part for their “repair” qualities, as OECs are found to migrate and associate with extending axons and are proposed to provide permissive conditions for axon bridging beyond the injury site [20], [38], [47], [39]. Importantly, grafted OECs are shown to migrate preferentially toward the lesion site in the damaged CNS [18]. In the present study, data from in vitro assays showed that both LPS-induced reactive astrocytes and glial scar tissue promote the migration of cultured OECs. Furthermore, in the spinal cord contralateral hemisection model, OECs injected rostral to lesion site were shown eventually to migrate from the site of grafting centripetally toward the glial scar and into lesion epicenter.



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