Secretory MPP3 reinforce myeloid differentiation trajectory and amplify myeloid cell production

Kang, Yoon-A; Paik, Hyojung; Zhang, Si Yi; Chen, Jonathan; Warr, Matthew R.; Fan, Rong; Passegué, Emmanuelle

Recent lineage tracing analyses revealed multipotent progenitors (MPP) to be major functional contributors to steady-state hematopoiesis (1–6). However, we are still lacking a precise resolution of myeloid differentiation trajectories and cellular heterogeneity in MPPs. Here, we found that myeloid-biased MPP3 (2, 3) are functionally and molecularly heterogeneous, with a distinct subset of myeloid-primed secretory cells with high endoplasmic reticulum (ER) volume and FcγR expression. We show that FcγR+/ERhigh MPP3 are a transitional population for rapid production of granulocyte/macrophage progenitors (GMP), which directly amplify myelopoiesis through inflammation-triggered secretion of cytokines in the local bone marrow (BM) microenvironment. Our results identify a novel regulatory function for a subset of secretory MPP3 that controls myeloid differentiation through lineage-priming and cytokine production, and act as a self-reinforcing amplification compartment in stress and disease conditions. One-Sentence Summary A secretory subset of multipotent hematopoietic progenitors augment myelopoiesis in stress and diseases conditions.