Hematopoietic Development of Human Pluripotent Stem Cells

Blood development proceeds through several waves of hematopoietic progenitors with unclear lineage relationships, which convolute the understanding of the process. Thinking of the hematopoietic precursors as the “blood germ layer” can integrate these waves into a unified hematopoietic lineage that originates in the yolk sac, the earliest site of blood development. Hematopoietic differentiation of pluripotent stem cells (PSCs) reflects to a certain extent the complexities of the yolk sac hematopoiesis. In the unified version of blood issue development, the PSC-derived hematopoiesis can also generate post-yolk sac hematopoietic progenitors. To do this, the differentiation has to be arranged for the reproduction of the intraembryonic hematopoiesis. Inflammatory signaling was recently shown to be actively engaged in blood ontogenesis. In addition, a highly recapitulative differentiation of human PSCs was found to spontaneously ignite intense sterile inflammation that has both instructive and destructive roles in the hPSC-hematopoiesis. Inflammatory induction of blood progenitors during hPSC-derived hematopoietic development has to be properly contained. A possible explanation of problems associated with in vitro blood development is the failure of inflammation containment and resolution.