Regulation of RhoA by STAT3 coordinates glial scar formation

The Journal of Cell Biology, 2017 · DOI: https://doi.org/10.1083/jcb.201610102 · Published: August 7, 2017

Simple Explanation

Scarring is a general tissue response after injury, which separates injured areas from healthy tissue and promotes wound healing. In response to various central nervous system (CNS) insults, lesion-proximal, reactive astrocytes form a glial scar, working in concert with secreted molecules found in the lesion. Understanding how the transcription factor signal transducer and activator of transcription–3 (STAT3) controls glial scar formation may have important clinical implications. We show that astrocytic STAT3 is associated with greater amounts of secreted MMP2, a crucial protease in scar formation. By specific targeting of lesion-proximal, reactive astrocytes in Nestin-Cre mice, we show that reduction of PTEN rescues glial scar formation in Nestin-Stat3+/− mice. These findings reveal novel intracellular signaling mechanisms underlying the contribution of reactive astrocyte dynamics to glial scar formation.

Study Duration

Not specified

Participants

Mice

Evidence Level

Not specified

Key Findings

1
Astrocytic STAT3 is associated with greater amounts of secreted MMP2, a crucial protease in scar formation.
2
STAT3 inhibits the small GTPase RhoA and thereby controls actomyosin tonus, adhesion turnover, and migration of reactive astrocytes, as well as corralling of leukocytes in vitro.
3
Reduction of phosphatase and tensin homologue (PTEN) levels in STAT3-CKO rescues reactive astrocytes dynamics in vitro.

Research Summary

Understanding how the transcription factor signal transducer and activator of transcription–3 (STAT3) controls glial scar formation may have important clinical implications. We show that astrocytic STAT3 is associated with greater amounts of secreted MMP2, a crucial protease in scar formation. Moreover, we report that STAT3 inhibits the small GTPase RhoA and thereby controls actomyosin tonus, adhesion turnover, and migration of reactive astrocytes, as well as corralling of leukocytes in vitro. These findings reveal novel intracellular signaling mechanisms underlying the contribution of reactive astrocyte dynamics to glial scar formation.

Practical Implications

Targeting PTEN

The deleterious action of astrocytic PTEN in glial scar formation suggests that the therapeutic value of targeting PTEN may extend beyond its direct neuronal action.

STAT3 and RhoA

Understanding the regulation of RhoA by STAT3 may have additional significance in the context of SCI, as STAT3 activation after injury may help to constrain the activation of RhoA.

Nestin-Cre mice

Nestin-CCE mouse enables specific labeling of scar-forming reactive astrocytes in the spinal cord, and thus constitutes a unique tool for their analysis.

Study Limitations

1
The reason for the reduced phosphorylation of ezrin in STAT3-CKO astrocytes is unknown.
2
Although PTEN IR is very weak and sparse in the sham spinal cord, contusive SCI induced strong up-regulation of PTEN IR.
3
Although the seclusion of the various nonneural cells that invade lesion centers has been shown to rely on STAT3-dependent reorientation of astrocytic processes, the molecular mechanisms underlying the effect of STAT3 remains unknown.

Your Feedback

Was this summary helpful?

Back to Spinal Cord Injury