Epidermal growth factor preserves myelin and promotes astrogliosis after intraventricular hemorrhage

Abstract

Intraventricular hemorrhage (IVH) leads to reduced myelination and astrogliosis of the white matter in premature infants. No therapeutic strategy exists to minimize white matter injury in survivors with IVH. Epidermal growth factor (EGF) enhances myelination, astrogliosis, and neurologic recovery in animal models of white matter injury. Here, we hypothesized that recombinant human (rh) EGF treatment would enhance oligodendrocyte precursor cell (OPC) maturation, myelination, and neurological recovery in preterm rabbits with IVH. In addition, rhEGF would promote astrogliosis by inducing astroglial progenitor proliferation and GFAP transcription. We tested these hypotheses in a preterm rabbit model of IVH and evaluated autopsy samples from human preterm infants. We found that EGF and EGFR expression were more abundant in the ganglionic eminence relative to the cortical plate and white matter of human infants and that the development of IVH reduced EGF levels, but not EGFR expression. Accordingly, rhEGF treatment promoted proliferation and maturation of OPCs, preserved myelin in the white matter, and enhanced neurological recovery in rabbits with IVH. rhEGF treatment inhibited Notch signaling, which conceivably contributed to OPC maturation. rhEGF treatment contributed to astrogliosis by increasing astroglial proliferation and upregulating GFAP as well as Sox9 expression. Hence, IVH results in a decline in EGF expression; and rhEGF treatment preserves myelin, restores neurological recovery, and exacerbates astrogliosis by inducing proliferation of astrocytes and enhancing transcription of GFAP and Sox9 in pups with IVH. rhEGF treatment might improve the neurological outcome of premature infants with IVH.

Human Cord Blood-Derived Unrestricted Somatic Stem Cell Infusion Improves Neurobehavioral Outcome in a Rabbit Model of Intraventricular Hemorrhage

“…C, D) was similar to the A1 astrocytes induced by neuroinflammatory microglia and cytokines reported by Liddelow et al and in our recent publication. In contrast, USSC treatment resulted in an altered phenotype of GFAP‐positive astrocytes with little or no astrocyte process (Fig. E, F).…”

“…The same primer sets were used as described previously. Analysis was completed using the efficiency corrected ΔΔCT method and the data were presented in percentages. …”

“…[14,33] Analysis was completed using the efficiency corrected ΔΔCT method and the data were presented in percentages. [34] Protein Blot Analyses Glial fibrillary acidic protein (GFAP) blot analyses was performed using our previously described method [20,33] after protein homogenates was made from fore-brain coronal slices were taken at the level of mid-septal nucleus from the three experimental groups. The primary antibodies used in the experiments included mouse monoclonal GFAP (catalog # G6171, St. Louis, MO).…”

Human and mouse iPSC-derived astrocyte subtypes reveal vulnerability in Vanishing White Matter

“…Even though hiPSC differentiation protocols have been developed to generate astrocytes with varying regional identities (Krencik and Zhang, 2011;Nadadhur et al, 2018), so far no protocols to produce white and grey matter astrocytes are in place, which is complicated by the lack of grey and white matter-specific markers. However, increased expression of EGF, FGFR3, GFAP, Nestin, S100B, GLT1, GLAST and CNTF has previously been associated with white matter astrocytes (Pringle et al, 2003;Vinukonda et al, 2016) (Dallner et al, 2002;Hassel et al, 2003;Steiner et al, 2007;Goursaud et al, 2009), as well as a smaller cell size and more complex processes in culture (Raff et al, 1983;Hughes et al, 1988;Landis et al, 1990;Bambrick et al, 1996;Haas et al, 2012). Here we presented protocols for human and mouse grey and white matter-like astrocytes.…”

Autologous Cord Blood in Children with Cerebral Palsy: A Review

“…Some of the soluble factors have been proposed for adjuvant stem cell therapy, including granulocyte colony stimulating factor (GCSF), brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), and glial cell line-derived neurotrophic factor (GDNF) ( Table 1). In particular, BDNF, GDNF, and GCSF are involved in the development, regeneration, and survival of neurons [33][34][35][36][37]. In a rodent model of HIE, MSCs exerted neuroprotective effects by enhancing autophagy through the BDNF/mTOR signaling pathway [38].…”