Notch1 signaling mediated dysfunction of bone marrow mesenchymal stem cells derived from cyanotic congenital heart disease

Bone marrow mesenchymal stem cells (BMSCs) derived from cyanotic congenital heart disease (CCHD) exhibit deficient multi-lineage differentiation potential due to the abnormal accumulation of D-galactose. However, the underlying mechanisms have not yet been explored. Here, the multi-lineage differentiation potential of the BMSCs from CCHD and non-CCHD (NCHD) patients were assessed. BMSCs from CCHD patients exhibited inferior multi-lineage differentiation potential with reduced Notch1 protein and mRNA level. Bisulfite sequencing PCR results showed the methylation level of Notch1 promoter was raised, which inhibited the binding of NF-Ya. Exposure BMSCs from NCHD patients with D-galactose under hypoxia (4% O₂) decreased the expression of Notch1. And activating Notch1 partially restored the deficient BMSCs of CCHD patients. In conclusion, the impaired multi-lineage differentiation potential of BMSCs from CCHD patients is owing to the decreased Notch1 level with a remarkable hypermethylation in its promoter region. Activated Notch1 signaling pathway could partially restore the deficient BMSCs in the CCHD patients, which may provide a new method on cell therapy in patients with CCHD.

Keywords: Bone marrow mesenchymal stem cells; Cyanotic congenital heart disease; D-galactose; Hypermethylation; Notch1.