Transforming Growth Factor α Transforms Astrocytes to a Growth-Supportive Phenotype after Spinal Cord Injury

Abstract

Astrocytes are both detrimental and beneficial for repair and recovery after spinal cord injury (SCI). These dynamic cells are primary contributors to the growth-inhibitory glial scar, yet they are also neuroprotective and can form growth-supportive bridges upon which axons traverse. We have shown that intrathecal administration of transforming growth factor alpha (TGFα) to the contused mouse spinal cord can enhance astrocyte infiltration and axonal growth within the injury site, but the mechanisms of these effects are not well understood. The present studies demonstrate that the epidermal growth factor receptor (EGFR) is upregulated primarily by astrocytes and glial progenitors early after SCI. TGFα directly activates the EGFR on these cells in vitro, inducing their proliferation, migration, and transformation to a phenotype that supports robust neurite outgrowth. Overexpression of TGFα in vivo by intraparenchymal adeno-associated virus injection adjacent to the injury site enhances cell proliferation, alters astrocyte distribution and facilitates increased axonal penetration at the rostral lesion border. To determine if endogenous EGFR activation is required after injury, SCI was also performed on Velvet (C57BL/6J-EgfrVel/J) mice, a mutant strain with defective EGFR activity. The affected mice exhibited malformed glial borders, larger lesions, and impaired recovery of function, indicating that intrinsic EGFR activation is necessary for neuroprotection and normal glial scar formation after SCI. By further stimulating precursor proliferation and modifying glial activation to promote a growth permissive environment, controlled stimulation of EGFR at the lesion border may be considered in the context of future strategies to enhance endogenous cellular repair following injury.

Fgf-Dependent Glial Cell Bridges Facilitate Spinal Cord Regeneration in Zebrafish

“…Interestingly, unipolar or bipolar GFAPexpressing cells (presumed radial glia) have been identified as the principal source of neurogenesis in the adult mouse (Garcia et al, 2004), revealing the proneurogenic effect of directing astrocyte differentiation into these radial glia. Experiments using astrocyte conditioned medium suggested that astrocytes secrete factors that may influence their ability to regain neuronal progenitor potential and dedifferentiate into radial glia (Yang et al, 2009) and TGF-␣ is one factor has been shown to drive astrocyte bipolar morphology in vitro (Zhou et al, 2001;White et al, 2011). EGF is an additional secreted factor that has been implicated in the dedifferentiation of rat astrocytes in culture (Yu et al, 2006).…”

The glial scar in spinal cord injury and repair

“…Further study has demonstrated that EGFR induces reactive astrocytes to migrate, undergo hypertrophy, and form a glial scar through activation of the Rheb-mToR signal pathway [50] . Deprivation of EGFR activity in mice results in malformed glial borders and larger lesions after SCi [51] . in addition, EGFR ligands, such as EGF and transforming growth factor-alpha (TGF-alpha), stimulate astrocytes to secrete CSPGs to further form the glial scar [52] .…”

Cell biology of spinal cord injury and repair

“…Various means of reactivating neuron-intrinsic growth programs are emerging, including modulating specific genetic pathways ( Figure 3A and discussed above), providing neuronal cell bodies with specific growth factors (150) or inflammatory factors (51,55,151), or stimulating neuronal activity (152). There is a growing list of chemoattractive growth factors that stimulate and guide regrowth of specific axons after SCI, including BDNF and NT3 for sensory axons (19,88), GDNF for propriospinal axons (89), and IGF1 for corticospinal axons (153), as well as pleotropic growth factors such as FGF and EGF that act in beneficial but undefined ways (154)(155)(156). Modulating axonal cytoskeleton may improve growth cone formation and axon regeneration (38,157,158).…”