Immunodeficiency reduces neural stem/progenitor cell apoptosis and enhances neurogenesis in the cerebral cortex after stroke

Abstract

Acute inflammation in the poststroke period exacerbates neuronal damage and stimulates reparative mechanisms, including neurogenesis. However, only a small fraction of neural stem/progenitor cells survives. In this report, by using a highly reproducible model of cortical infarction in SCID mice, we examined the effects of immunodeficiency on reduction of brain injury, survival of neural stem/progenitor cells, and functional recovery. Subsequently, the contribution of T lymphocytes to neurogenesis was evaluated in mice depleted for each subset of T lymphocyte. SCID mice revealed the reduced apoptosis and enhanced proliferation of neural stem/progenitor cells induced by cerebral cortex after stroke compared with the immunocompetent wild-type mice. Removal of T lymphocytes, especially the CD4(+) T-cell population, enhanced generation of neural stem/progenitor cells, followed by accelerated functional recovery. In contrast, removal of CD25(+) T cells, a cell population including regulatory T lymphocytes, impaired functional recovery through, at least in part, suppression of neurogenesis. Our findings demonstrate a key role of T lymphocytes in regulation of poststroke neurogenesis and indicate a potential novel strategy for cell therapy in repair of the central nervous system.

Ischemia-induced neural stem/progenitor cells express pyramidal cell markers

“…However, the projecting pyramidal cortical neurons forming long-distance neuronal circuitry have been derived from these progenitor cells without much success, although a recent publication has demonstrated that ES cell-derived NSCs can differentiate into pyramidal cells that integrate into the adult poststroke cortex [11]. Although it would still be challenging to accomplish cortical neurogenesis after permanent ischemic stroke in vivo, we have shown that adequate support of iNSPCs in the in-vivo environment of the poststroke cortex (e.g., regulation of endothelial cells [7,9] and inflammatory cells [8]) could promote the proliferation of iNSPCs and enhance neurogenesis and cortical functional recovery.…”

“…Previously, we demonstrated that immunodeficiency reduces neural stem/progenitor cell apoptosis and enhances neurogenesis in the cerebral cortex after stroke [8]. In this study, to determine cell proliferation in vivo, 7-week-old male SCID mice were injected with 5-bromo-2-deoxyuridinine (BrdU) to visualize regenerating neurons.…”

Immunopathogenetic Aspects of Ischemic Stroke

“…Данный эффект воспроизводился при переносе спленоцитов или CD4 + T-клеток от толерантных мышей интактным животным [4]. Позитивный эффект Тreg может быть обусловлен не только их иммунорегуляторной активностью, направлен-ной на подавление воспалительного процесса, но и стимулирующим влиянием на стволовые клет-ки, поскольку деплеция Тreg сопровождается ос-лаблением нейрогенеза [104]. Другим механиз-мом Тreg может быть стимулирующее действие этих клеток на постишемическую неоваскуляри-зацию [141].…”

Immune System Modulation of Germinal and Parenchymal Neural Progenitor Cells in Physiological and Pathological Conditions

“…Notably, similar to the healthy conditions, defined subpopulations of T cells contribute to modulate germinal niche functioning at early stages after injury. Removal of the whole CD4+ T cell population results in increased precursor/neuroblast generation few days after stroke, while depletion of the only Treg lymphocytes suppresses neurogenesis and reduces functional recovery (Saino et al, 2010). In contrast, promotion of Treg homing to the ischemic brain enhances NSC and neuroblast survival (Ishibashi et al, 2009).…”

“…In contrast, promotion of Treg homing to the ischemic brain enhances NSC and neuroblast survival (Ishibashi et al, 2009). At variance with non-pathological conditions, post-injury T cell effects appear to modulate pro-inflammatory cytokine secretion by activated endothelial cells rather than being mediated by microglial functions (Saino et al, 2010;Ishibashi et al, 2009). …”