title: Mitotic History Reveals Distinct Stem Cell Populations and Their Contributions to Hematopoiesis.
abstract: Homeostasis of short-lived blood cells is dependent on rapid proliferation of immature precursors. Using a conditional histone 2B-mCherry-labeling mouse model, we characterize hematopoietic stem cell (HSC) and progenitor proliferation dynamics in steady state and following several types of induced stress. HSC proliferation following HSC transplantation into lethally irradiated mice is fundamentally different not only from native hematopoiesis but also from other stress contexts. Whereas transplantation promoted sustained, long-term proliferation of HSCs, both cytokine-induced mobilization and acute depletion of selected blood cell lineages elicited very limited recruitment of HSCs to the proliferative pool. By coupling mCherry-based analysis of proliferation history with multiplex gene expression analyses on single cells, we have found that HSCs can be stratified into four distinct subtypes. These subtypes have distinct molecular signatures and differ significantly in their reconstitution potentials, showcasing the power of tracking proliferation history when resolving functional heterogeneity of HSCs.
authors.affiliation: Division of Molecular Hematology, Department of Laboratory Medicine, Medical Faculty, Lund University, Klinikgatan 26, BMC B12, 22184 Lund, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Säwén
authors.affiliation: Division of Molecular Hematology, Department of Laboratory Medicine, Medical Faculty, Lund University, Klinikgatan 26, BMC B12, 22184 Lund, Sweden; StemTherapy, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lang
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Division of Hematology/Oncology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02116, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Mandal
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Division of Hematology/Oncology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02116, USA.
authors.forename: Derrick J
authors.initials: DJ
authors.lastname: Rossi
authors.affiliation: Division of Molecular Hematology, Department of Laboratory Medicine, Medical Faculty, Lund University, Klinikgatan 26, BMC B12, 22184 Lund, Sweden; StemTherapy, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
authors.forename: Shamit
authors.initials: S
authors.lastname: Soneji
authors.affiliation: Division of Molecular Hematology, Department of Laboratory Medicine, Medical Faculty, Lund University, Klinikgatan 26, BMC B12, 22184 Lund, Sweden; Hemato-Linné, Lund University, 22184 Lund, Sweden; StemTherapy, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. Electronic address: david.bryder@med.lu.se.
authors.forename: David
authors.initials: D
authors.lastname: Bryder
mesh_terms: D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D004317:Doxorubicin / Q000633:toxicity; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006410:Hematopoiesis / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D016130:Immunophenotyping; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008938:Mitosis; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014184:Transplantation, Homologous; D000097573:Red Fluorescent Protein
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004317:Doxorubicin; D008164:Luminescent Proteins; D000097573:Red Fluorescent Protein