Chromatin site specific accessibility: a microtopography regulated door into the stem cell fate [Hi-C]

Biomaterials engineered to mimic extracellular matrix (ECM) topography play a pivotal role in tissue engineering. Previous research indicates that certain biomimetic topographies can guide stem cells towards multiple specific lineages. However, the mechanisms by which these topographic cues prime the multilineage differentiation remain largely elusive. In this study, we show that topography influences nuclear tension in MSCs through a mechanotransductive feedback mechanism, which in turn reshapes chromatin accessibility patterns, finally determines the stem cell lineage commitment. When cultured on an aligned substrate, MSCs show high cytoskeletal tension along the fibre direction, resulting in anisotropic nucleus tensile stress. This further leads to the opening of chromatin sites related to neurogenic, myogenic, and tenogenic genes by the regulation of transcription factors such as TLX. On the other hand, when MSCs are lied on a random substrate, they experience isotropic nucleus stress, leading to the opening of chromatin sites related to osteogenic and chondrogenic genes through the regulation of RUNX family transcription factors. Collectively, our results show that aligned and random topography induce site specific chromatin stretching and lineage specific gene expressing in MSCs, leading to their priming for specific lineages. Our study thus proposes a novel concept for topographic cues influencing on cell behavior and fate during tissue reconstitution and regeneration.