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Microglia-mediated pericytes migration and fibroblast transition via S1P/S1P3/YAP signaling pathway after spinal cord

Ziyuan Yu1, Huabin Zhang1, Linxi Li1

  • 1Guangzhou Med Univ, Inst Neurosci, Dept Neurosurg, Affiliated Hosp 2, Guangzhou 510260, PR China.

Experimental Neurology
|June 12, 2024
PubMed

Insights

Microglia-derived Sphingosine-1-phosphate (S1P) promotes pericyte migration and scar formation after spinal cord injury (SCI). Targeting the S1P/S1P3/YAP pathway with inhibitors like TY52156 may offer a novel therapeutic strategy for SCI.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Regenerative Medicine

Background:

  • Platelet-derived growth factor receptor β positive (PDGFRβ+) pericytes contribute to fibrotic scar formation after spinal cord injury (SCI).
  • The precise mechanisms driving pericyte migration and their transition into fibroblasts post-SCI remain largely unknown.
  • Understanding these mechanisms is crucial for developing effective SCI treatments.

Purpose of the Study:

  • To elucidate the spatiotemporal relationship between microglia and pericytes following SCI.
  • To investigate the role of the Sphingosine kinase-1 (SPHK1)/Sphingosine-1-phosphate (S1P) pathway in pericyte migration and fibroblast transition.
  • To identify potential therapeutic targets for mitigating fibrotic scarring after SCI.

Main Methods:

  • Analysis of microglia-pericyte distribution at 3 and 7 days post-injury (dpi) in a SCI model.
  • Assessment of Sphingosine kinase-1 (SPHK1) expression in microglia and Sphingosine-1-phosphate (S1P) levels in the spinal cord.
  • In vitro studies using cell cultures to examine the effects of S1P on pericyte behavior and YAP signaling.
  • Evaluation of the S1P/S1P3/YAP pathway and the impact of the S1P3 inhibitor TY52156.

Main Results:

  • A significant correlation was observed between microglia and pericytes at 3 and 7 dpi.
  • Increased SPHK1 expression in microglia led to elevated S1P levels, promoting pericyte migration and fibroblast transition.
  • In vitro, elevated S1P signaling via S1P receptor 3 (S1P3) inhibited YAP phosphorylation, promoted its nuclear translocation, and increased α-SMA and COL1 expression.
  • The S1P3 specific inhibitor TY52156 effectively blocked these effects in vitro.

Conclusions:

  • The SPHK1/S1P pathway in microglia plays a critical role in pericyte migration and fibrotic scar formation post-SCI.
  • The S1P/S1P3/YAP signaling axis is a key mediator of pericyte-to-fibroblast transition.
  • Targeting the S1P/S1P3/YAP pathway, potentially with inhibitors like TY52156, represents a promising therapeutic strategy for reducing SCI-induced fibrosis.
Keywords:
Fibrous scarsMicrogliaPericyteSphingosine-1-phosphateSpinal cord injury

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