Rhee C, Scadden EW, Wong LP, Schiroli G, Mazzola MC, Chea PL, Kato H, Hoyer FF, Mistry M, Lee BK, Kim J, Nahrendorf M, Mansour MK, Sykes DB, Sadreyev RI, Scadden DT. 2023. Limited plasticity of monocyte fate and function associated with epigenetic scripting at the level of progenitors. Blood. 142(7):658-674. Pubmed: 37267513 DOI:10.1182/blood.2023020257


Myeloid cell heterogeneity is known, but whether it is cell-intrinsic or environmentally-directed remains unclear. Here, an inducible/reversible system pausing myeloid differentiation allowed the definition of clone-specific functions that clustered monocytes into subsets with distinctive molecular features. These subsets were orthogonal to the classical/nonclassical categorization and had inherent, restricted characteristics that did not shift under homeostasis, after irradiation, or with infectious stress. Rather, their functional fate was constrained by chromatin accessibility established at or before the granulocyte-monocyte or monocyte-dendritic progenitor level. Subsets of primary monocytes had differential ability to control distinct infectious agents in vivo. Therefore, monocytes are a heterogeneous population of functionally restricted subtypes defined by the epigenome of their progenitors that are differentially selected by physiologic challenges with limited plasticity to transition from one subset to another.
© 2023 by The American Society of Hematology.

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David Scadden’s laboratory is dedicated to discovering the principles governing blood cell production, with the ultimate goal of guiding the development of therapies for blood disorders and cancer.

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