Phagocytosing differentiated cell-fragments is a novel mechanism for controlling somatic stem cell differentiation within a short time frame

Abstract

Stem cells undergo cytokine-driven differentiation; however, this process often takes longer than several weeks to complete. A novel mechanism for somatic stem cell differentiation via phagocytosing ‘model cells’ (apoptotic differentiated cells) was found to only require a short time frame. Pluripotent-like Muse cells, multipotent mesenchymal stem cells, and neural stem cells phagocytosed apoptotic differentiated cells via different phagocytic receptor subsets than macrophages. The phagocytosed-differentiated cellderived contents (e.g. transcription factors) were quickly released into the cytoplasm, translocated into the nucleus and bound to promoter regions of the stem cell genomes. Within 24~36 h, the cells expressed lineage-specific markers corresponding to the phagocytosed-differentiated cells, both in vitro and in vivo . At one week, the gene expression profiles were similar to those of the authentic differentiated cells and expressed functional markers. Differentiation was limited to the inherent potential of each cell line: triploblastic-, adipogenic-/chondrogenic-, and neural-lineages, respectively. Disruption of phagocytosis, either by phagocytic receptor inhibition via small interfering RNA or Annexin V treatment, impeded differentiation in vitro and in vivo . Collectively, our study uncovers a simple way to directly transfer differentiation-directing factors to trigger rapid differentiation of somatic stem cells into the target cell lineage.