Pre-implantation factor promotes neuroprotection by modulating long non-coding RNA H19 of the neuronal stem cells

Purpose:

Successful therapies for periventricular leukomalacia (PVL) in premature infants are lacking. Post-injury activation of neural stem cells (NSCs) represents an attractive strategy and long non-coding RNA H19 is a candidate to regulate cell differentiation. Since synthetic-PreImplantation factor (sPIF) protects against neuronal disorders, we posit that sPIF activates NSCs after injury by modulating H19.

Methods:

A mouse model of PVL (n = 20) was electroporated with a pCAG-Cre plasmid (labelling NSCs). A H19-plasmid (pCMV-H19CA) was used to increase H19 activity in NSCs. Cell lines (Immature oligodendrocytes MO13.13) were treated with sPIF (200nM; 48h) or siRNA H19 and evaluated by qRT-PCR. Animals were evaluated by MRI, immunohistochemistry and in-situ hybridization. Significance was set at p < 0.05 *p < 0.05, **p < 0.01, ***p < 0.001.

Results:

In animals, both sPIF and H19CA ameliorated myelin loss significantly (Fig. 1A-B). In cell lines, sPIF increased mRNA expression of oligodendrocyte markers in H19-dependent manner (Fig. 1C). sPIF also increased H19 expression in the brain (Fig. 1D).

Conclusion:

sPIF activates NSCs and prevents myelin loss by modulating H19. Given the FDA Fast Track designation and safety data of sPIF in First in Human Trial (NCT02239562), clinical trials to prevent or treat PVL can be envisioned.

Abb. 1: sPIF improves myelin loss after injury and stimulates oligodendrocyte differentiation