Clonal and Quantitative In Vivo Assessment of Hematopoietic Stem Cell Differentiation Reveals Strong Erythroid Potential of Multipotent Cells

Hematopoiesis is arguably one of the best understood stem cell systems; however, significant challenges remain to reach a consensus understanding of the lineage potential, heterogeneity, and relationships of hematopoietic stem and progenitor cell populations. To gain new insights, we performed quantitative analyses of mature cell production from hematopoietic stem cells (HSCs) and multiple hematopoietic progenitor populations. Assessment of the absolute numbers of mature cell types produced by each progenitor cell revealed a striking erythroid dominance of all myeloid-competent progenitors assessed, accompanied by strong platelet reconstitution. All populations with myeloid potential also produced robust numbers of red blood cells and platelets in vivo. Clonal analysis by single-cell transplantation and by spleen colony assays revealed that a significant fraction of HSCs and multipotent progenitors have multilineage potential at the single-cell level. These new insights prompt an erythroid-focused model of hematopoietic differentiation. [Display omitted] •RBCs are the predominant cell type produced by multipotent hematopoietic progenitors•All cell types with myeloid potential also produced RBCs and platelets in vivo•Single HSCs and MPPF cells are capable of multilineage hematopoietic reconstitution•Erythroid cell production emerges as a default hematopoietic fate In this article, Forsberg and colleagues use quantitative reconstitution assays to demonstrate that all myeloid-competent progenitor cells also contribute to erythroid and platelet production. Single-cell in vivo analyses showed that hematopoietic stem cells and multipotent progenitors are clonally multipotent. These results suggest that erythropoiesis is a default hematopoietic fate and challenges current views on hematopoietic lineage potential and fate decisions.