Functionally Distinct Subsets of Lineage-Biased Multipotent Progenitors Control Blood Production in Normal and Regenerative Conditions.
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Abstract | 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 toward 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. |
Year of Publication | 2015
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Journal | Cell Stem Cell
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Volume | 17
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Issue | 1
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Pages | 35-46
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Date Published | 2015 Jul 02
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ISSN | 1875-9777
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URL | |
DOI | 10.1016/j.stem.2015.05.003
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PubMed ID | 26095048
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PubMed Central ID | PMC4542150
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Grant list | R01 HL092471 / HL / NHLBI NIH HHS / United States
F32 HL106989 / HL / NHLBI NIH HHS / United States
K01 DK098315 / DK / NIDDK NIH HHS / United States
T32 AI007334 / AI / NIAID NIH HHS / United States
R01 GM109031 / GM / NIGMS NIH HHS / United States
12765 / Cancer Research UK / United Kingdom
Cancer Research UK / United Kingdom
K01DK098315 / DK / NIDDK NIH HHS / United States
R01 CA180778 / CA / NCI NIH HHS / United States
MR/M008975/1 / Medical Research Council / United Kingdom
F32HL106989 / HL / NHLBI NIH HHS / United States
MC_PC_12009 / Medical Research Council / United Kingdom
R01HL092471 / HL / NHLBI NIH HHS / United States
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