Epigenetic landscape model and signaling pathway of cell differentiation driven by extrinsic photobiomodulation combined with microisland.

Extrinsic photobiomodulation (EPM) combined with microisland offers a universal approach to induce and direct mesenchymal stem cell differentiation. In this study, the dependencies of differentiation of human umbilical cord Wharton's Jelly mesenchymal stem cells driven by this method on various EPM parameters as well as initial cell stemness were investigated and an epigenetic landscape model was established to explain the results consistently. Furthermore, the signal cascade pathway was studied and it was found that photosensitizer binding to endoplasmic reticulum was the primary receptor and the increase of nuclear Ca2+ level was the second messenger. Moreover, the number, size, and concentration of bromodomain-containing protein 4 (BRD4)-containing nuclear condensates were reduced when the cells were on microislands and treated by EPM, indicating this change was involved in the alteration of epigenetic modification that led to the conversion of cell phenotype.