Mechanisms of ischaemic neural progenitor proliferation: a regulatory role of the HIF-1α-CBX7 pathway

Aims Investigations of the molecular mechanisms of hypoxia- and ischaemia-induced endogenous neural progenitor cell (NPC) proliferation have mainly focused on factors secreted in response to environmental cues. However, little is known about the intrinsic regulatory machinery underlying the self-renewing division of NPCs in the brain after stroke. Methods and results Polycomb repressor complex 1-chromobox7 (CBX7) has emerged as a key regulator in several cellular processes including stem cell self-renewal and cancer cell proliferation. The hypoxic environment triggering NPC self-renewal after CBX7 activation remains unknown. In this study, we found that the upregulation of CBX7 during hypoxia and ischaemia appeared to be from hypoxia-inducible factor-1 alpha (HIF-1 alpha) activation. During hypoxia, the HIF-1 alpha-CBX7 cascade modulated NPC proliferation in vitro. NPC numbers significantly decreased in CBX7 knockout mice generated using CRISPR/Cas9 genome editing. Conclusions We provided the novel insight that CBX7 expression is regulated through HIF-1 alpha activation, which plays an intrinsically modulating role in NPC proliferation.