Notch-HEY2 signaling pathway contributes to the differentiation of CD34 hematopoietic-like stem cells from adult peripheral blood insulin-producing cells after the treatment with platelet-derived mitochondria.

Previous works characterized a novel cell population from adult human peripheral blood, designated peripheral blood insulin-producing cells (PB-IPC). PB-IPC displayed the pluripotent potential of differentiations after the treatment with platelet-derived mitochondria and gave rise to three germ layer-derived cells such as the mitochondrion-induced CD34 hematopoietic stem cells (HSC)-like cells (miCD34 HSC). To determine the molecular mechanism underlying the differentiation of miCD34 cells, mechanistic studies established that MitoTracker Deep Red-labeled mitochondria could enter into the PB-IPC in a dose-dependent manner. Blocking Notch signaling pathway with a γ-secretase inhibitor, DAPT, markedly inhibited the proliferation of PB-IPC and improved the differentiation of miCD34 HSC. Additionally, treatment with platelet-derived mitochondria can reprogram the differentiation of PB-IPC into miCD34 HSC through inhibition of the Notch/HEY2 signaling pathway, as demonstrated by blocking experiments with HEY2 small interfering RNA (siRNA). The data indicated that Notch signaling pathway contributes to the miCD34 HSC differentiation, thus advancing our understanding of the mitochondrial reprogramming and the potential treatment of human hematopoietic disease.