Tgfp Expression In Cns Wounds

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There is little or no expression of TGF-P 1 in the adult CNS neural parenchyma. The protein is exclusively restricted to the mesenchymal support structures such as the choroid plexus and meninges. By contrast, TGF-P2 and TGF-P3 are both widely, coincidentally, and constitutively expressed by neurons and glia as well as by the CNS mesenchymal support structures.46 The precise functions of TGF-Ps in the intact and injured CNS remain to be defined, but in vitro studies have indicated potential gliogenic, neurotrophic, angiogenic, and fibrogenic activities.47-53

After a CNS injury that breaches the blood-brain barrier, TGF-P 1 and TGF-P2 are released from platelets and secreted from cells of the monocyte/macrophage lineage at the earliest stages of the injury response. In a number of in vivo experimental CNS injury paradigms, the local expression of TGF-P1 increases.17-22 For

FIGURE 8.6 A/B Localisation of immunoreactive A: TGF-P1 and B: TGF-P2 in injured cerebral cortex parenchyma. Five days postlesion significant levels of immunoreactive TGF-P1 and TGF-P2 are seen in neurons (closed arrows) and astrocytes (open arrows) of the neuropil bordering the wound.

example, within traumatic wounds of the rat cerebral cortex and spinal cord, the influx of haematogenous TGF-P1 and TGF-P2 is rapidly followed by a transient upregulation of expression of both peptides by injury-responsive cells;1821 so that after injury, TGF-P1 and TGF-P2 proteins are localised to astrocytes, microglia, neurons, vascular endothelial cells, and macrophages (Figure 8.6). Further, the localisation of TGF-P1 and TGF-P2 mRNA to choroid plexus epithelial cells and the measurement of significantly increased levels of both proteins in the cerebrospinal fluid (Logan, A. and Berry, M., unpublished observations) indicate a supply of factors to the damaged neuropil posthaemorrhage, both via the CSF as well as by local synthesis within the wound. In accordance with the observations in rodent experimental models, TGF-P 1 levels have also been investigated in a preliminary study of the cerebrospinal fluid of humans with severe traumatic brain injury;54 levels are dramatically raised, with the highest values observed in the first few days postinjury. TGF-P1 levels also rise in human brain tissue damaged by hypoxic/ischaemic insults,55 suggesting a neuroprotective role as well as stimulating angiogenesis and scarring.

In vivo studies are now establishing a major role for TGF-Ps in the repair of the injured brain. In addition to inducing fibrosis and reactive gliosis,21 TGF-Ps probably have other homeostatic functions. They may play an important role in CNS microvas-culature angiogenesis,56 which is needed for the neovascularisation of the scar tissue. The TGF-Ps may probably also act as inflammatory mediators by recruiting, priming, and activating cells of the immune system, including microglia.5758 Nerve growth factor (NGF) synthesis is also induced by TGF-P 1,59 probably contributing to the reported neurotrophic activity of the cytokine, since NGF not only has a trophic effect on CNS neurons, but also stimulates astrocytes to become reactive.53 The ability of TGF-Ps to upregulate their own synthesis as well as that of other cytokines suggests a mechanism for the initiation and amplification of the trophic regulatory cascade that occurs in wounds.60

Since the foetal and neonatal CNS heals without scarring, one might predict that TGF-Ps would be absent from such wounds. This is not the case. The intact immature CNS expresses all three isoforms of TGF-P at significant levels and a role for these factors in regulation of neuronal migration and differentiation as well as glial proliferation is suggested.48-53 Furthermore, there is a rapid though transient increase in TGF-P 1 expression within damaged perinatal CNS tissue (Logan, A. and Berry, M., unpublished observations). The question of why the immature CNS does not scar despite the presence of potent fibrogenic factors remains to be fully answered. However, it may relate to the developmental competence of target cells to respond appropriately to the cytokines and the presence or absence of other trophins. It is clear that individual growth factors do not act in isolation and that cellular responses are dependent on the context in which trophins are presented, and this is particularly true of the TGF-Ps.

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How To Reduce Acne Scarring

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