Oligodendrocyte progenitor proliferation is disinhibited following traumatic brain injury in LIF heterozygous mice

Abstract

Traumatic brain injury (TBI) is a significant problem that affects ∼500,000 children each year. As cell proliferation is disturbed by injury and is required for normal brain development, we investigated how a pediatric closed head injury (CHI) would affect the progenitors of the subventricular zone (SVZ). Additionally, we evaluated the contribution of Leukemia Inhibitory Factor (LIF) using LIF-heterozygous mice (LIF Het), as LIF is an injury-induced cytokine, known to influence neurogenesis and gliogenesis. CHI’s were performed on P20 LIF Het and WT mice. Ki-67 staining and stereology revealed that cell proliferation increased ∼250% in injured LIF Het mice compared to the 30% increase observed in injured WT mice at 48 h post CHI. Furthermore, Olig2+ cell proliferation increased in the SVZ and white matter of LIF Het injured mice at 48 h recovery. Using an 8-color flow cytometry panel, the proliferation of three distinct multipotential progenitors were greater in LIF Het injured mice compared to WT injured mice. Early oligodendrocyte progenitor cell (OPC) proliferation was 6-fold higher in LIF Het injured mice compared to WT injured mice. In vitro, addition of LIF decreased overall cell proliferation and OPC proliferation compared to controls. Addition of LIF to OPC cultures induced an increase of phospho-Akt after 20 minutes and an increase of phospho-S6RP at 20 and 40 minutes of exposure, suggesting that LIF stimulates the mammalian target of Rapamycin pathway. Altogether, our data provide new insights into the regulatory role of LIF in suppressing neural progenitor cell proliferation after a mild TBI.Main PointsOPC proliferation is dis-inhibited in LIF haplodeficient mice.LIF directly inhibits glial progenitor cell proliferation.LIF stimulates the mTOR pathway.

Leukemia Inhibitory Factor Is Required for Subventricular Zone Astrocyte Progenitor Proliferation and for Prokineticin-2 Production after a Closed Head Injury in Mice

“…However, when we used this same flow panel to evaluate the NSCs after CHI, we did not observe any changes in the proportions of NSCs in the SVZ or in the percentage of EdU+ cells. These data support the conclusion that a single CHI is not sufficient to activate the NSCs of the SVZ, 43 likely because it is much less severe. 43 However, a limitation to these studies is that we have only evaluated the NSCs at 24, 48, and 96 h of recovery from the CHI.…”

“…These data support the conclusion that a single CHI is not sufficient to activate the NSCs of the SVZ, 43 likely because it is much less severe. 43 However, a limitation to these studies is that we have only evaluated the NSCs at 24, 48, and 96 h of recovery from the CHI. As the NSCs have a very slow cell-FIG.…”

“…In the studies described here and in a companion article, 43 we found that the bona fide NSCs are not proliferating in response to this mild injury, as they do in more severe injury models. 12 We used Glast to identify the astrocyte progenitors by flow cytometry.…”

An Integrative Approach to the Current Treatment of HIV-Associated Neurocognitive Disorders and the Implementation of Leukemia Inhibitor Factor as a Mediator of Neurocognitive Preservation

“…It has been shown that the LIF regulates the formation of neurons in various regions of the brain, including the olfactory bulb and subventricular zone. The LIF has been found to discourage neurogenesis in these studies by acting directly on neural stem cells (NSCs) and causing them to stay in their undifferentiated state for a longer period of time [18,19]. The results suggest that the presence or absence of the LIF is a crucial factor when it comes to determining the levels of neurogenesis in the nervous system.…”