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

Abstract

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-1β 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.

MicroRNA‐140‐5p inhibitor attenuates memory impairment induced by amyloid‐ß oligomer in vivo possibly through Pin1 regulation

“…Coronal sections were stained as previously described. 30 , 31 Briefly, following deparaffinizing and hydrating with xylene and descending graded ethanol, the sections were incubated in 0.1% cresyl Violet solution (Nissl Staining, Sigma‐Aldrich), for 6 min at 58°C. Subsequently, they were dehydrated using increasing concentrations of ethanol, cleared by xylene, and cover‐slipped.…”

Contemplating IL‐6, a double‐edged sword cytokine: Which side to use for stroke pathology?

“…Similarly, human embryonic stem cell‐derived and umbilical cord MSCs decrease IL‐6 mRNA in murine models of middle cerebral artery occlusion. This decrease in IL‐6 may be relevant to the increased neurogenesis, increased angiogenesis, and decreased apoptosis seen in these treated animals 36,37 . Given the role of IL‐6 in inflammation following stroke, it is understandable that blocking this cytokine prior to potential exacerbated inflammation offers therapeutic benefit.…”

Therapeutic gene delivery by mesenchymal stem cell for brain ischemia damage: Focus on molecular mechanisms in ischemic stroke

“…Neurotrophic components, such as GDNF, NGF, and BDNF, are endogenous macromolecules that primarily support nervous system cell development and growth 83,84 . Long‐term memory and synaptic plasticity are other areas in which they are involved.…”

“…In addition to its anti‐inflammatory properties, the primary source of functional recovery following the use of MSC is the transfer of neurotrophic factors into the brain, which in turn stimulates neurogenesis as well as neuroprotection. Molecular research has demonstrated the presence of NTFs such GDNF, NGF, and BDNF in exosomes generated from MSCs 84,88–90 …”