Priming with interleukin-1α and chemical hypoxia modulates the mesenchymal stem cell secretome to dampen microglial inflammation and promote neuroprotection.

BACKGROUND AND PURPOSE: We hypothesised that dual priming of human bone marrow-derived human mesenchymal stem cells (hBMSCs) with interleukin-1alpha (IL-1α) and CoCl2 (a hypoxia mimetic) would modulate their therapeutic efficacy for hypoxic-ischaemic conditions.

EXPERIMENTAL APPROACH: hBMSCs were primed individually or in combination. To test the anti-inflammatory and cytoprotective properties, primed-hBMSCs-derived conditioned media (CM) was applied to lipopolysaccharide (LPS)-treated BV2 microglial cells (inflammation model) and BV2 cells exposed to oxygen glucose deprivation (OGD) (hypoxic injury model). The neuroprotective effect was evaluated by assessing neuronal death (using neuron-like cells [NLCs]) following exposure to OGD/reoxygenation (OGD/R) in the presence of various CMs.

KEY

RESULTS

Priming significantly altered hBMSCs' secretion profiles. IL-1α triggered significant (P < 0.05) release of inflammatory mediators/cytokines, notably TNF-α, ICAM-1 and G-CSF. Except for G-SCF, dual-priming did not potentiate their release. While single priming with either IL-1α or hypoxia-mimetic did not induce remarkable secretion of the neurotrophins β-NGF and BDNF, the dual-priming caused a potentiated increase (P < 0.05) in the secretion of these neurotrophins. In the LPS model, CM from dual-primed hBMSCs significantly reduced the secretion of pro-inflammatory cytokines, TNF-α and IL-6. In the OGD/R model, priming did not significantly influence the marked reduction (P < 0.05) of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. Lastly, CMs from primed hBMSCs reduced neuronal cytotoxicity, yet only CM from dual-primed hBMSCs significantly (P < 0.05) restored metabolic activity in NLCs following OGD/R.

CONCLUSIONS AND IMPLICATIONS: These findings highlight dual priming as a promising strategy for optimising MSC-based approaches for hypoxic-ischaemic conditions.