Paracrine Factors Secreted by MSCs Promote Astrocyte Survival Associated With GFAP Downregulation After Ischemic Stroke via p38 MAPK and JNK

J Cell Physiol. 2015 Oct;230(10):2461-75. doi: 10.1002/jcp.24981.

Abstract

Astrocytes are critical for ischemic stroke, and understanding their role in mesenchymal stem cell (MSC)-mediated protection against ischemic injury is important. The paracrine capacity of MSCs has been proposed as the principal mechanism contributing to the protection and repair of brain tissue. In the present study, an in vitro oxygen-glucose deprivation (OGD) model was used to mimic ischemic injury. OGD-induced astrocytes were reperfused with MSC-conditioned medium (MSC-CM) or co-cultured with MSCs for 24 h to create an environment abundant in paracrine factors. The results indicated that both situations could protect astrocytes from apoptosis, increase cell metabolic activity, and reduce glial fibrillary acidic protein (GFAP) overexpression; however, the effects of co-culturing with MSCs were more positive. Paracrine factors suppressed the activation of p38 MAPK, JNK, and their downstream targets p53 and STAT1. Inhibition of p38 MAPK, JNK, p53, and STAT1 attenuated astrocyte injury and/or GFAP upregulation. Activation of p38 MAPK and JNK suppressed the beneficial effects of paracrine factors, resulting in decreased survival and GFAP overexpression. These results suggest that paracrine factors inhibit p38 MAPK and JNK, and most likely by regulating their downstream targets, p53 and STAT1, to promote astrocyte survival associated with GFAP downregulation after ischemic stroke in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Brain Ischemia / metabolism*
  • Cells, Cultured
  • Disease Models, Animal
  • Down-Regulation
  • Glial Fibrillary Acidic Protein / metabolism*
  • MAP Kinase Kinase 4 / metabolism*
  • Mesenchymal Stem Cells / metabolism*
  • Paracrine Communication
  • Rats, Wistar
  • Stroke / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Glial Fibrillary Acidic Protein
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4