Functionally Distinct Subsets of Lineage-Biased Multipotent Progenitors Control Blood Production in Normal and Regenerative Conditions

Abstract

SUMMARY Despite great advances in understanding the mechanisms underlying blood production, lineage specification at the level of multipotent progenitors (MPPs) remains poorly understood. Here, we show that MPP2 and MPP3 are distinct myeloid-biased MPP subsets that work together with lymphoid-primed MPP4 cells to control blood production. We find that all MPPs are produced in parallel by hematopoietic stem cells (HSCs), but with different kinetics and at variable levels depending on hematopoietic demands. We also show that the normally rare myeloid-biased MPPs are transiently overproduced by HSCs in regenerating conditions, hence supporting myeloid amplification to rebuild the hematopoietic system. This shift is accompanied by a reduction in self-renewal activity in regenerating HSCs and reprogramming of MPP4 fate towards the myeloid lineage. Our results support a dynamic model of blood development in which HSCs convey lineage specification through independent production of distinct lineage-biased MPP subsets that, in turn, support lineage expansion and differentiation.

TLR5 signaling in murine bone marrow induces hematopoietic progenitor cell proliferation and aids survival from radiation

“…Markers for LT-HSCs, ST-HSCs, and MPP1-MPP4 are previously described. 14,25,26 In cell proliferation assays, intracellular staining of allophycocyanin-conjugated anti-BrdU and 7-aminoactinomycin D (7-AAD) were performed following surface staining. Stained cells were analyzed on a BD Fortessa flow cytometer.…”

“…7,11,13,14 these subtypes were impacted by flagellin treatment, we performed flow cytometry analysis on LSK cells from flagellin-or PBS-treated WT B6 mice using the recently defined signaling lymphocytic activation molecule (SLAM) code, which is capable of distinguishing LT-HSC, ST-HSC, and MPP subtypes. 14,25,26 This cellular identification protocol indicated that flagellin did not increase the level or alter the proliferative status of LT-HSCs (supplemental Figure 7A-C). Rather, flagellin treatment drove the proliferation of ST-HSCs and myeloid precursors MPP2 and especially MPP3, whose levels increased 10-fold following flagellin treatment ( Figure 5A-E).…”

“…14,[31][32][33][34][35] We hypothesized that flagellin's induction of MPP3 cell proliferation may underlie its radioprotective effect and, hence, that administration of exogenous purified MPP3 cells might have the ability to aid survival in a scenario in which administered bone marrow was insufficient for this purpose. To test this hypothesis, we lethally irradiated C57BL/6 mice and transferred 1 3 10 5 whole bone marrow cells (the number of cells needed, but not sufficient, to rescue them), whereas giving a higher number of such bone marrow cells allowed them survive.…”

“…7,[11][12][13] Among LSK cells, LT-HSC retain long-term renewal ability, while ST-HSC and MPPs only differentiate to various mature lineages. 7,11,14 Repopulation of neutrophils in peripheral blood is critical for protection against infection after irradiation or bone marrow transplantation. 15 Hence, we hypothesized that flagellin might activate bone marrow cells to induce either LT-HSC or hematopoietic progenitor cell proliferation and differentiation.…”

The stem cell niche finds its true north

“…She showed that during blood regeneration, HSCs are induced to overproduce myeloid-biased multipotent progenitors (Pietras et al, 2015). An important consequence of the activation of this myeloid regeneration axis is the formation of defined granulocyte/ macrophage progenitor clusters in the bone marrow cavity, which drive the local overproduction of granulocytes.…”