title: Functionally Distinct Subsets of Lineage-Biased Multipotent Progenitors Control Blood Production in Normal and Regenerative Conditions.
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.
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Pietras
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Reynaud
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Yoon-A
authors.initials: YA
authors.lastname: Kang
authors.affiliation: Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, CA 94720, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Carlin
authors.affiliation: Cambridge University Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust and MRC Cambridge Stem Cell Institute, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Calero-Nieto
authors.affiliation: Departments of Medicine and Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Leavitt
authors.affiliation: Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, CA 94720, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Stuart
authors.affiliation: Cambridge University Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust and MRC Cambridge Stem Cell Institute, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: passeguee@stemcell.ucsf.edu.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Passegué
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D065150:Cellular Reprogramming; D015870:Gene Expression; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000145:classification / Q000166:cytology / Q000502:physiology; D054503:Lymphoid Progenitor Cells / Q000145:classification / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D039902:Multipotent Stem Cells / Q000145:classification* / Q000166:cytology* / Q000502:physiology; D023461:Myeloid Progenitor Cells / Q000145:classification / Q000166:cytology / Q000502:physiology; D012038:Regeneration