β1-Integrin alters ependymal stem cell BMP receptor localization and attenuates astrogliosis after spinal cord injury.
Astrogliosis after spinal cord injury (SCI) is a major impediment to functional recovery. More than half of new astrocytes generated after SCI are derived from ependymal zone stem cells (EZCs). We demonstrate that expression of β1-integrin increases in EZCs following SCI in mice. Conditional knock-out of β1-integrin increases GFAP expression and astrocytic differentiation by cultured EZCs without altering oligodendroglial or neuronal differentiation. Ablation of β1-integrin from EZCs in vivo reduced the number of EZC progeny that continued to express stem cell markers after SCI, increased the proportion of EZC progeny that differentiated into GFAP+ astrocytes, and diminished functional recovery. Loss of β1-integrin increased SMAD1/5/8 and p38 signaling, suggesting activation of BMP signaling. Coimmunoprecipitation studies demonstrated that β1-integrin directly interacts with the bone morphogenetic protein receptor subunits BMPR1a and BMPR1b. Ablation of β1-integrin reduced overall levels of BMP receptors but significantly increased partitioning of BMPR1b into lipid rafts with increased SMAD1/5/8 and p38 signaling. Thus β1-integrin expression by EZCs reduces movement of BMPR1b into lipid rafts, thereby limiting the known deleterious effects of BMPR1b signaling on glial scar formation after SCI.
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 h.north.scheler@northwestern.edu.
Hilary A
HA
North
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
Liuliu
L
Pan
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
Tammy L
TL
McGuire
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
Sarah
http://orcid.org/0000-0002-5674-3124
S
Brooker
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
John A
JA
Kessler
D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D052004:Bone Morphogenetic Protein Receptors / Q000187:drug effects*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004805:Ependyma / Q000166:cytology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D019012:Integrin beta1 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000187:drug effects*; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy* / Q000473:pathology
D005904:Glial Fibrillary Acidic Protein; D019012:Integrin beta1; D052004:Bone Morphogenetic Protein Receptors
BMP; astrocyte; integrin; neural stem cell; spinal cord injury