Reduction of the Cell Cycle Length by Decreasing G1 Phase and Cell Cycle Reentry Expand Neuronal Progenitor Cells in the Subventricular Zone of Adult Rat after Stroke

Abstract

A critical determinant of proliferation of progenitor cells is the duration of the cell division cycle. Stroke increases proliferation of progenitor cells in the subventricular zone (SVZ). Using cumulative and single S-phase labeling with 5-bromo-2′-deoxyuridine, we examined cell cycle kinetics of neural progenitor cells in the SVZ after stroke. In nonstroke rats, 20% of the SVZ cell population was proliferating. However, stroke significantly increased dividing cells up to 31% and these cells had a cell cycle length ( T_c) of 15.3 h, significantly ( P < 0.05) shorter than the 19 h Tc in nonstroke SVZ cells. Few terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive cells were detected in the SVZ cells of nonstroke and stroke groups, suggesting that the majority of dividing cells in the SVZ do not undergo apoptosis. Cell cycle phase analysis revealed that stroke substantially shortened the length of the G₁ phase (9.6 h) compared with the G₁ phase of 12.6 h in nonstroke SVZ cells ( P < 0.03). This reduction in G₁ contributes to stroke-induced reduction of T_c because no significant changes were detected on the length of S, G₂ and M phases between two groups. Furthermore, compared with progenitor cells in nonstroke SVZ (10%), a greater proportion (14%) of progenitor cells in stroke SVZ reentered the cell cycle after mitosis ( P < 0.05). These results show that an increase in proliferating progenitor cells in the SVZ contributes to stroke-induced neurogenesis and this increase is regulated by shortening the length of the cell cycle, decreasing the G₁ phase and increasing cell cycle reentry.