Leukemia inhibitory factor participates in the expansion of neural stem/progenitors after perinatal hypoxia/ischemia

Abstract

Subsequent to perinatal hypoxia/ischemia there is an increase in the number of neural stem/progenitor cells (NSP) within the subventricular zone. Gene expression analyses have implicated Notch signaling in the expansion of these tripotential cells but there are limited data as to which signals are stimulating Notch activation. There is evidence that the LIFR/gp130 receptor heterodimer induces Notch1 to maintain NSP populations during normal development. LIF and CNTF bind to these receptor components and they coordinate injury responses in the CNS. Therefore, the aim of these studies was to investigate whether CNTF and/or LIF participate in NSP expansion in the SVZ after H/I as well as to characterize the downstream events that regulate NSP numbers. We report that LIF mRNA is induced 48 hours post insult by 13 fold but that it returns almost to baseline by 72 hours. Commensurate with increased LIF expression there is a corresponding increase in phosphorylated STAT-3 within the SVZ. Modeling the changes that occur in vivo, we show that LIF induces STAT-3 phosphorylation in neurospheres to enhance Delta-like-1 and Notch1 expression as well as to increase Notch1 activation. LIF also expands neurosphere number and size in vitro. Whereas CNTF can mimic the effects of LIF in vitro, CNTF expression in the SVZ was unchanged during recovery from H/I. Cumulatively, these data implicate LIF and not CNTF in the expansion of NSPs in the SVZ after perinatal brain injury. As both LIF expression and the endogenous regenerative response after brain injury are time-delimited, these findings provide insights into strategies to expand the endogenous pool of NSPs to repopulate the damaged brain.

Reduced EGFR signaling in progenitor cells of the adult subventricular zone attenuates oligodendrogenesis after demyelination

“…Growth factors that are secreted by endothelial cells (Gama Sosa et al, 2007;Rosenstein and Krum, 2006) as well as by other glial cells (Aschner, 1996;Suzumura et al, 2006;Sen and Levison, 2006) during development and under pathological conditions (Ferrer et al, 1996;Lisovoski et al, 1997;Jin et al, 2002;Covey and Levison, 2007) are crucial regulators of progenitor cell mobilization. Previous reports demonstrated upregulation of several growth factors in the CC after demyelination, including HB-EGF and TGF-alpha (Ferrer et al, 1996;Lisovoski et al, 1997;Aguirre et al, 2007).…”

The role of the leukemia inhibitory factor receptor in neuroprotective signaling

“…However, LIF exerts anti-neurogenic effects in the CNS by inhibiting the terminal differentiation of murine olfactory receptor neurons as well as neurons in the primary visual cortex (Engelhardt et al, 2017; Moon et al, 2002). LIF increases neural stem cell (NSC) populations and enhances self-renewal by inhibiting differentiation, which allows NSCs to aid in neural repair during injury (Bauer & Patterson, 2006; Buono, Vadlamuri, Gan, & Levison, 2012; Covey & Levison, 2007). Using a gene microarray, Wright et al demonstrated that these anti-differentiation effects on NSC populations following LIF treatment occurred due to changes in the expression of over 200 genes (Wright et al, 2003).…”

Glial Development: The Crossroads of Regeneration and Repair in the CNS

“…Fibroblast growth factor 2 (FGF2), epidermal growth factor (EGF), and leukemia inhibitory factor (LIF) are upregulated in the SVZ after hypoxic insult (Covey and Levison, 2007; Ganat et al, 2002; Scafidi et al, 2014). These factors promote OL generation from OPCs, as well as OL maturation and survival during normal development.…”