Abstract
Astrogliosis with glial scar formation after damage to the nervous system is a major impediment to axonal regeneration and functional recovery. The present study examined the role of β1-integrin signaling in regulating astrocytic differentiation of neural stem cells. In the adult spinal cord β1-integrin is expressed predominantly in the ependymal region where ependymal stem cells (ESCs) reside. β1-integrin signaling suppressed astrocytic differentiation of both cultured ESCs and subventricular zone (SVZ) progenitor cells. Conditional knockout of β1-integrin enhanced astrogliogenesis both by cultured ESCs and by SVZ progenitor cells. Previous studies have shown that injection into the injured spinal cord of a self-assembling peptide amphiphile that displays an IKVAV epitope (IKVAV-PA) limits glial scar formation and enhances functional recovery. Here we find that injection of IKVAV-PA induced high levels of β1-integrin in ESCs in vivo, and that conditional knockout of β1-integrin abolished the astroglial suppressive effects of IKVAV-PA in vitro. Injection into an injured spinal cord of PAs expressing two other epitopes known to interact with β1-integrin, a Tenascin C epitope and the fibronectin epitope RGD, improved functional recovery comparable to the effects of IKVAV-PA. Finally we found that the effects of β1-integrin signaling on astrogliosis are mediated by integrin linked kinase (ILK). These observations demonstrate an important role for β1-integrin/ILK signaling in regulating astrogliosis from ESCs and suggest ILK as a potential target for limiting glial scar formation after nervous system injury.
Highlights
After injury to the nervous system, astrocytes undergo a series of morphologic and molecular changes that facilitate sealing of the blood brain barrier and functional recovery [10,11,42]
We report a series of observations that demonstrate an important role for b1-integrin/integrin linked kinase (ILK) signaling in regulating astrocytic differentiation of ependymal stem cells (ESCs) and suggest ILK as a potential target for limiting glial scar formation after nervous system injury
To directly test whether the suppressive effects on astrocyte development were due to the expression of b1-integrin, we examined the effects of IKVAV-peptide amphiphile (PA) on neural stem/progenitor cells (NSCs) in which b1-integrin was knocked out using Adeno-Cre retrovirus as described above (Figure 3G)
Summary
After injury to the nervous system, astrocytes undergo a series of morphologic and molecular changes that facilitate sealing of the blood brain barrier and functional recovery [10,11,42]. IKVAV-PA profoundly suppressed astrocytic differentiation of cultured neural stem/progenitor cells (NSCs) [47]. Integrin receptor subunit [14] which is the most ubiquitously expressed integrin subunit This suggested the possibility that b1integrin signaling might be involved in astrogliosis after SCI. Higher levels of b1-integrin expression by cultured NSCs correlate with a PLOS ONE | www.plosone.org b1-Integrin Signaling Suppresses Astrocytic Differentiation higher capability for self-renewal mediated via the MAPK cascade [8]. We asked whether the effects of IKVAV-PA in limiting the glial scar might be mediated by interactions with b1-integrin expressed by ESCs, and what downstream signaling pathways might be involved. We report a series of observations that demonstrate an important role for b1-integrin/ILK signaling in regulating astrocytic differentiation of ESCs and suggest ILK as a potential target for limiting glial scar formation after nervous system injury
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