Enhancement of endogenous neurogenesis in ephrin-B3 deficient mice after transient focal cerebral ischemia

Abstract

Cerebral ischemia stimulates endogenous neurogenesis. However, the functional relevance of this phenomenon remains unclear because of poor survival and low neuronal differentiation rates of newborn cells. Therefore, further studies on mechanisms regulating neurogenesis under ischemic conditions are required, among which ephrin-ligands and ephrin-receptors (Eph) are an interesting target. Although Eph/ephrin proteins like ephrin-B3 are known to negatively regulate neurogenesis under physiological conditions, their role in cerebral ischemia is largely unknown. We therefore studied neurogenesis, brain injury and functional outcome in ephrin-B3−/− (knockout) and ephrin-B3+/+ (wild-type) mice submitted to cerebral ischemia. Induction of stroke resulted in enhanced cell proliferation and neuronal differentiation around the lesion site of ephrin-B3−/− compared to ephrin-B3+/+ mice. However, prominent post-ischemic neurogenesis in ephrin-B3−/− mice was accompanied by significantly increased ischemic injury and motor coordination deficits that persisted up to 4 weeks. Ischemic injury in ephrin-B3−/− mice was associated with a caspase-3-dependent activation of the signal transducer and activator of transcription 1 (STAT1). Whereas inhibition of caspase-3 had no effect on brain injury in ephrin-B3+/+ animals, infarct size in ephrin-B3−/− mice was strongly reduced, suggesting that aggravated brain injury in these animals might involve a caspase-3-dependent activation of STAT1. In conclusion, post-ischemic neurogenesis in ephrin-B3−/− mice is strongly enhanced, but fails to contribute to functional recovery because of caspase-3-mediated aggravation of ischemic injury in these animals. Our results suggest that ephrin-B3 might be an interesting target for overcoming some of the limitations of further cell-based therapies in stroke.

EphB4 Regulates Self-Renewal, Proliferation and Neuronal Differentiation of Human Embryonic Neural Stem Cells in Vitro

“…Eph tyrosine kinase receptors and their ephrin ligands have been identified as important regulators of neural stem/progenitor cells differentiation [13, 16, 44-46]. In a prior study, Katakowski et al reported that EphB2 promotes a neuronal fate in adult subventricular neural precursor cells [19].…”

EphrinB2 Activation Enhances Vascular Repair Mechanisms and Reduces Brain Swelling After Mild Cerebral Ischemia

“…Furthermore, different Eph-ephrin molecules have shown to be activated after stroke: EphA2 activation after stroke contributes to BBB damage and neuronal cell death, whereas astrocytic ephrinA5 inhibits axonal sprouting, and ephrinB3 deficiency enhances poststroke neurogenesis. [17][18][19] In contrast, the role of ephrinB2/EphB4 signaling in ischemic stroke is still unexplored.…”

Transduction of Neural Precursor Cells with TAT-Heat Shock Protein 70 Chaperone: Therapeutic Potential Against Ischemic Stroke after Intrastriatal and Systemic Transplantation

“…One day before induction of stroke, animals were trained before the beginning of the actual tests on day 7, 14, 28, and 56. Both rota rod and tight rope test were performed as previously described [40]. Using the rota rod test, animals were put on an accelerating treadmill (TSE Systems, Bad Homburg, Germany, www.tse-systems.com; 3-cm diameter) with an accelerating speed of 4-40 rpm.…”

“…For the tight rope test, animals were placed on a 60-cm long rope grasping the string with their forepaws. Maximum test time was 60 seconds, and results were scored from 0 (minimum) to 20 (maximum) according to a validated score [40], depending on the time animals spent on the rope and whether or not they reached the platform. Rota rod and tight rope tests were performed twice at each time point and means were calculated.…”