TY - JOUR
T1 - Functionally Distinct Subsets of Lineage-Biased Multipotent Progenitors Control Blood Production in Normal and Regenerative Conditions
AU - Pietras, Eric M.
AU - Reynaud, Damien
AU - Kang, Yoon A.
AU - Carlin, Daniel
AU - Calero-Nieto, Fernando J.
AU - Leavitt, Andrew D.
AU - Stuart, Joshua A.
AU - Göttgens, Berthold
AU - Passegué, Emmanuelle
N1 - Funding Information:
We thank Dr. C. Nerlov (Oxford University) for Pu.1-eYFP mice, Dr. F. de Savage (Genentech) for Mpl −/− mice, M. Sánchez-Castillo for help with t-SNE and discriminant classification analyses, M. Kissner and M. Lee for management of our flow cytometry core facility, B. King for initial analyses of Mpl −/− mice, S. Wang for help with MegaCult experiments, Gladstone Genomics Core for microarray processing, and all members of the E.P. laboratory for critical insights and suggestions. This work was supported by NIH awards F32HL106989 and K01DK098315 (to E.M.P.); grants from Leukaemia and Lymphoma Research and Cancer Research UK and core support by the Wellcome Trust (to B.G.); and NIH grant R01HL092471, a Rita Allen Scholar Award, and a Leukemia Lymphoma Society Scholar Award (to E.P.).
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84937023176&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2015.05.003
DO - 10.1016/j.stem.2015.05.003
M3 - Article
C2 - 26095048
AN - SCOPUS:84937023176
VL - 17
SP - 35
EP - 46
JO - Cell Stem Cell
JF - Cell Stem Cell
SN - 1934-5909
IS - 1
ER -