Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury

In the injured central nervous system (CNS), reactive astrocytes form a glial scar and are considered to be detrimental for axonal regeneration, but their function remains elusive. Here we show that reactive astrocytes have a crucial role in wound healing and functional recovery by using mice with a selective deletion of the protein signal transducer and activator of transcription 3 (Stat3) or the protein suppressor of cytokine signaling 3 (Socs3) under the control of the Nes promoterenhancer (Nes-Stat3 –/– , Nes-Socs3 –/– ). Reactive astrocytes in Nes-Stat3 –/– mice showed limited migration and resulted in markedly widespread infiltration of inflammatory cells, neural disruption and demyelination with severe motor deficits after contusive spinal cord injury (SCI). On the contrary, we observed rapid migration of reactive astrocytes to seclude inflammatory cells, enhanced contraction of lesion area and notable improvement in functional recovery in Nes-Socs3 –/– mice. These results suggest that Stat3 is a key regulator of reactive astrocytes in the healing process after SCI, providing a potential target for intervention in the treatment of CNS injury. Because the regenerative capability of the mammalian CNS is poor, limited functional recovery occurs during the chronic phase of SCI. At the subacute phase of SCI, however, gradual functional recovery is observed to some extent in both rodents and humans (except in cases of complete paralysis). The mechanism behind this functional recovery remains unclear. Here, we investigated this issue by focusing on the action of reactive astrocytes in a mouse model of SCI. To interpret the process of paralysis improvement in the subacute phase, we examined serial histological sections of contused spinal cords and followed motor function for 6 weeks after injury in wild-type mice and found that the area of neural cell loss gradually enlarged in a rostral-caudal direction within a few days after SCI (acute phase) and a portion of Hu-expressing neurons were positive for cleaved caspase-3, indicating that the secondary injury process lasted for several days in this model (Supplementary Fig. 1 online) during which we observed limited functional recovery (Fig. 1a). Astrocytes surrounding the lesion underwent a typical change of hypertrophy, process extension and increased expression of intermediate filaments such as GFAP and Nestin by 7 d after SCI (Fig. 1b), characteristic of ‘reactive astrocytes.’ Notably, these astrocytes eventually migrated centripetally to the lesion