Hippocampal neuroprotection mediated by secretome of human mesenchymal stem cells against experimental stroke

Aims Regenerative medicine literature has demonstrated that the therapeutic potentials of mesenchymal stem cells (MSCs) in experimental stroke are attributed to secreted bioactive factors rather than to cell replacement. Here, we explored the effects of secretome or conditioned medium (CM) derived from human embryonic stem cell-derived MSCs (hESC-MSCs) on hippocampal neurogenesis, inflammation, and apoptosis in experimental stroke. Methods Ischemic stroke was induced by right middle cerebral artery occlusion (MCAO) in male Wistar rats, and CM was infused either one time (1-h post-stroke; CM1) or three times (1-, 24-, and 48-h post-stroke; CM3) into left lateral ventricle. Neurogenesis markers (Nestin, Ki67, Doublecortin, and Reelin) were assessed at transcript and protein levels in the dentate gyrus of the hippocampus on day seven following MCAO. In parallel, changes in the gene expression of markers of apoptosis (Bax and Bim, as well as an anti-apoptotic marker of Bcl2), inflammation (IL-1 beta and IL-6, as well as IL-10 as an anti-inflammatory cytokine), trophic factors (BDNF, GDNF, NGF, and NT-3), and angiogenesis (CD31 and VEGF) in the hippocampus were assessed. Results Our results demonstrate that CM3 treatment could stimulate neurogenesis and angiogenesis concomitant with inhibition of inflammation, apoptosis, and neuronal loss in ischemic brains. Furthermore, rats treated with CM3 exhibited upregulation in neurotrophic factors. Conclusion Our results suggest that hESC-MSC-CM could promote neurogenesis and protect brain tissue from ischemic injury, partly mediated by induction of angiogenesis and neurotrophic factors and inhibition of inflammatory and apoptotic factors expression.