Redefining hematopoietic progenitor cells and reforming the hierarchy of hematopoiesis

Abstract

Deciphering the mechanisms underlying progenitor cell differentiation and cell-fate decisions is critical for answering fundamental questions regarding hematopoietic lineage commitment. Here, we redefine the entire spectrum of original hematopoietic progenitor cells (HPCs) using a comprehensive transcriptional atlas that effectively delineates the transitional progenitors. This is the first study to fully distinguish the transitional state along hematopoietic progenitor cell differentiation, reconciling previous controversial definitions of common myeloid progenitors (CMPs), granulocyte-monocyte progenitors (GMPs), and lymphoid-primed multipotent progenitors (LMPPs). Moreover, plasma progenitor cells are identified and defined. Transcription factors associated with key cell-fate decisions are identified at each level of the hematopoietic hierarchy, providing novel insights into the underlying molecular mechanisms. The hematopoietic hierarchy roadmap was reformed that reconciles previous models concerning pathways and branches of hematopoiesis commitment. Initial hematopoietic progenitors are simultaneously primed into megakaryocytic-erythroid, lymphoid, and neutrophilic progenitors during the first differentiation stage of hematopoiesis. During initial progenitor commitment, GATA2, HOPX, and CSF3R determine the co-segregation of the three transitional lineage branches. Two types of lineage-commitment processes occur during hematopoiesis: the megakaryocytic-erythroid lineage commitment process is continuous, while the lymphoid-lineage commitment is stepwise. Collectively, these results raise numerous possibilities for precisely controlling progenitor cell differentiation, facilitating advancements in regenerative medicine and disease treatment. HighlightsO_LIHematopoietic progenitors are redefined using a comprehensive transcriptional atlas. C_LIO_LICell fate decision-related transcription factors are revealed in the hematopoietic hierarchy. C_LIO_LIProgenitor lineage commitment includes continuous and stepwise processes. C_LIO_LIThe initial hematopoietic hierarchy is simultaneously primed into three lineages. C_LI