title: Transplanted murine long-term repopulating hematopoietic cells can differentiate to osteoblasts in the marrow stem cell niche.
abstract: Bone marrow transplantation (BMT) can give rise to donor-derived osteopoiesis in mice and humans; however, the source of this activity, whether a primitive osteoprogenitor or a transplantable marrow cell with dual hematopoietic and osteogenic potential, has eluded detection. To address this issue, we fractionated whole BM from mice according to cell surface immunophenotype and assayed the hematopoietic and osteopoietic potentials of the transplanted cells. Here, we show that a donor marrow cell capable of robust osteopoiesis possesses a surface phenotype of c-Kit(+) Lin(-) Sca-1(+) CD34(-/lo), identical to that of the long-term repopulating hematopoietic stem cell (LTR-HSC). Secondary BMT studies demonstrated that a single marrow cell able to contribute to hematopoietic reconstitution in primary recipients also drives robust osteopoiesis and LT hematopoiesis in secondary recipients. These findings indicate that LTR-HSC can give rise to progeny that differentiate to osteoblasts after BMT, suggesting a mechanism for prompt restoration of the osteoblastic HSC niche following BM injury, such as that induced by clinical BMT preparative regimens. An understanding of the mechanisms that regulate this differentiation potential may lead to novel treatments for disorders of bone as well as methods for preserving the integrity of endosteal hematopoietic niches.
authors.affiliation: Division of Oncology/Blood and Marrow Transplantation, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Ted J
authors.initials: TJ
authors.lastname: Hofmann
authors.forename: Satoru
authors.initials: S
authors.lastname: Otsuru
authors.forename: Roberta
authors.initials: R
authors.lastname: Marino
authors.forename: Valeria
authors.initials: V
authors.lastname: Rasini
authors.forename: Elena
authors.initials: E
authors.lastname: Veronesi
authors.forename: Alba
authors.initials: A
authors.lastname: Murgia
authors.forename: Jill
authors.initials: J
authors.lastname: Lahti
authors.forename: Kelli
authors.initials: K
authors.lastname: Boyd
authors.forename: Massimo
authors.initials: M
authors.lastname: Dominici
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Horwitz
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D010865:Pilot Projects; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055153:Stem Cell Niche
chemical_list: D019009:Proto-Oncogene Proteins c-kit