Membrane Progesterone Receptor α (mPRα/PAQR7) Promotes Survival and Neurite Outgrowth of Human Neuronal Cells by a Direct Action and Through Schwann Cell-like Stem Cells

We recently showed that membrane progesterone receptor alpha (mPR alpha/PAQR7) promotes pro-regenerative effects in Schwann cell-like adipose stem cells (SCL-ASC), an alternative model to Schwann cells for the promotion of peripheral nerve regeneration. In this study, we investigated how mPR alpha activation with the mPR-specific agonist Org OD 02-0 in SCL-ASC affected regenerative parameters in two neuronal cell lines, IMR-32 and SH-SY-5Y. In a series of conditioned medium experiments, we found that mPR activation of SCL-ASC led to increased neurite outgrowth, protection from cell death and increased expression of peripheral nerve regeneration markers (CREB3, ATF3, GAP43) in neuronal cell lines. These effects were stronger than the ones observed with the conditioned medium from untreated SCL-ASC. The addition of Org OD 02-0 to the untreated cell medium mimicked the effects of mPR activation of SCL-ASC on cell death, but not on neurite outgrowth. Therefore, the effect of Org OD 02-0 on neurite outgrowth is SCL-ASC-dependent, while its effect on cell survivability is likely due to the direct activation of mPRs on neuronal cells. SCL-ASC transfection with mPRa siRNA showed that this isoform is responsible for the beneficial effect on neurite outgrowth. Further experiments showed that SCL-ASC-dependent outcomes likely involved the release of BDNF and IGF-2 from these cells. The beneficial mPR alpha effect on neurite outgrowth was confirmed in co-culture conditions. These findings strengthen the hypothesis that mPR alpha could play a pro-regenerative role in SCL-ASC and be a therapeutic target for the promotion of peripheral nerve regeneration.

Automated summary

This study demonstrates that the activation of membrane progesterone receptor alpha (mPR alpha/PAQR7) promotes regenerative effects in Schwann cell-like adipose stem cells (SCL-ASC) by increasing neurite outgrowth, protecting against cell death, and increasing expression of peripheral nerve regeneration markers in neuronal cell lines. The effects are mediated through the release of BDNF and IGF-2 from SCL-ASC. These findings suggest that mPR alpha could be targeted therapeutically to promote peripheral nerve regeneration.