Effects of Transforming Growth Factor β₁, on Scar Production in the Injured Central Nervous System of the Rat

Abstract

In the central nervous system (CNS), nerve regeneration after traumatic injury fails. The formation of a dense fibrous scar is thought to restrict in part the growth of axonal projections, providing one of the many reasons that complete lesions of neural pathways in the adult mammalian CNS are rarely followed by significant functional recovery. In order to determine which mechanisms mediate scar formation in the CNS and to investigate whether they can be modulated in vim, we have attempted to define the potential role of trophic factors. Our previous studies have shown the focal elevation of transforming growth factor P1 (TGFP,) expression in lesioned CNS tissue. In the studies described here, we demonstrate that TGFP, participates in the scarring response in the rat brain. First, the elevated protein levels of TGFP, are localized to specific populations of injury-responsive cells in the traumatized CNS. Furthermore, the injection of TGFP, into the brains of injured rats causes a dramatic increase in the scarring response. Conversely, when neutralizing TGFP, antibodies are administered, the deposition of fibrous scar tissue and the formation of a limiting glial membrane that borders the lesion is significantly attenuated, thus establishing a role for the endogenous growth factor in regulation of the non-glial component of the scar. In implicating TGFP, in the scarring response in the CNS, the potential use for TGFP, antagonists as inhibitors of scar formation in the injured mammalian CNS is self-evident.

Endogenous Transforming Growth Factor β1 Suppresses Inflammation and Promotes Survival in Adult CNS

“…Such a mechanism could also be responsible for the decreased central axonal sprouting and functional recovery observed in the TGF␤1Ϫ/Ϫ mice, but indirect changes should not be excluded. For example, absence of TGF␤1 strongly enhances the astroglial and extracellular matrix responses that correlate inversely with central axonal sprouting (Logan et al, 1994;Galiano et al, 2001). Inhibition of TGF␤ signaling interferes with Schwann cell proliferation and cell death (D'Antonio et al, 2006), which could affect the speed of functional recovery after peripheral injury.…”

“…Although TGF␤1 levels are strongly and rapidly upregulated after different forms of injury like cortical incision, entorhinal lesion, ischemia, experimental allergic neuritis, or peripheral axotomy (Nichols et al, 1991;Klempt et al, 1992;Kiefer et al, 1993a,b;Logan et al, 1994), TGF␤1 is also present in moderately high levels even in the normal, uninjured adult brain (Lindholm et al, 1992), and could thus be involved in mediating the persistent downregulation of microglia and astrocytes in the absence of injury. To elucidate the function of endogenous TGF␤1 in the CNS, we examined the effects of TGF␤1 deficiency on the unlesioned adult brain and then extended these studies to an experimental model of CNS trauma and functional repair in the axotomized mouse facial motor nucleus.…”

TGF-β1 suppresses T cell infiltration and VP2 puff B mutation enhances apoptosis in acute polioencephalitis induced by Theiler's virus

“…The active form of TGF-β1 is known to stimulate the deposition of extracellular matrix proteins, such as laminin and fibronectin Noble and Border, 1997). Upregulation of the matrix proteins indicates that TGF-β1 in the tissue is biologically active (Logan et al, 1994;Wyss-Coray et al, 1995). Laminin is a consistent component of cerebral basement membrane, which is normally restricted to blood vessels, pia mater, ependyma and choroid plexus (Jucker et al, 1996).…”

Increased adenine nucleotide translocator 1 in reactive astrocytes facilitates glutamate transport

“…Astrocytes exposed to TGF-β1 increase expression of GFAP (Krohn et al, 1999;Reilly et al, 1998) as well as putative axon growth inhibitory ECM proteins such as tenascin and neurocan (Asher et al, 2000;Smith and Hale, 1997). Intracerebral cortical injection of TGF-β1 increases astrocytic production of the ECM molecules laminin and fibronectin in areas of reactive gliosis, and in vivo administration of TGF-β neutralizing antibodies reduces ECM deposition following brain injury (Logan et al, 1994; The molecular mechanisms of reactive gliosis, including the role of TGF-β1 in this process, are largely unexplored. Therefore, we employed differential display PCR (ddPCR) to identify genes specifically regulated by TGF-β1 in an in vivo model of reactive gliosis.…”