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.