title: Ability of circulating human hematopoietic lineage negative cells to support hematopoiesis.
abstract: Hematopoietic stem cell (HSC) self-renewal is regulated by osteoblast and/or endothelial cells within the hematopoietic niche. However, the true identity of the supporting cells and the nature of the secreted factors remain uncertain. We developed a novel mouse model and analyzed whether circulating human peripheral hematopoietic lineage negative/AP+ (lin-/AP+) cells support hematopoiesis in vivo. Thus, immunocompromised (Rag) mice expressing thymidine kinase (Tk) under the control of the 3.6Col1α1 promoter (Tk-Rag) were treated with ganciclovir, resulting in osteoblast progenitor cell ablation and subsequent loss of hematopoiesis (evaluated by measuring mouse Ter119+ erythroid cells). Following hematopoietic cell depletion, human bone marrow-derived marrow stromal cells (MSCs) or lin-/AP+ cells were infused into Tk-Rag mice and compared with saline infusions. Ganciclovir significantly reduced (7.4-fold) Ter119+ cells in the bone marrow of Tk-Rag mice compared to saline injections. Infusion of either MSCs or lin-/AP+ cells into ganciclovir-treated mice resulted in a 3.3-fold and 2.7-fold increase (P < 0.01), respectively, in Ter119+ cells compared to mice receiving saline. Relative to lin-/AP- cells, lin-/AP+ cells expressed high levels of mesenchymal, endothelial, and hematopoiesis supporting genes. Thus, human peripheral blood lin-/AP+ cells represent a novel cell type capable of supporting hematopoiesis in a manner comparable to MSCs.
authors.affiliation: Endocrine Research Unit, College of Medicine, Mayo Clinic, Rochester, Minnesota; Rheumatology Department, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Peris
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Roforth
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Nicks
authors.forename: Daniel
authors.initials: D
authors.lastname: Fraser
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.forename: Robert L
authors.initials: RL
authors.lastname: Jilka
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
authors.forename: Ulrike
authors.initials: U
authors.lastname: McGregor
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D019070:Cell Lineage; D005260:Female; D005434:Flow Cytometry; D015774:Ganciclovir / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D051379:Mice
chemical_list: D015774:Ganciclovir
keywords: ENDOTHELIAL CELLS; HEMATOPOIESIS; LIN−/AP+ CELLS; MESENCHYMAL CELLS; MOUSE MODEL