title: Deficiency of lipid phosphatase SHIP enables long-term reconstitution of hematopoietic inductive bone marrow microenvironment.
abstract: A dysfunctional bone marrow (BM) microenvironment is thought to contribute to the development of hematologic diseases. However, functional replacement of pathologic BM microenvironment through BM transplantation has not been possible. Furthermore, the study of hematopoietic inductive BM microenvironment is hampered by the lack of a functional nonhematopoietic reconstitution system. Here, we show that a deficiency of SH2-containing inositol-5'-phosphatase-1 (SHIP) in a nonhematopoietic host microenvironment enables its functional reconstitution by wild-type donor cells. This microenvironment reconstitution normalizes hematopoiesis in peripheral blood and BM and alleviates pathology of spleen and lung in the SHIP-deficient recipients. SHIP-deficient BM contains a significantly smaller population of multipotent stromal cells with distinct properties, which may contribute to the reconstitution by wild-type cells. We further demonstrate that it is the nonhematopoietic donor cells that are responsible for the reconstitution. Thus, we have established a nonhematopoietic BM microenvironment reconstitution system to functionally study specific cell types in hematopoietic niches.
authors.affiliation: Department of Pathology, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Olin D
authors.initials: OD
authors.lastname: Liang
authors.forename: Jiayun
authors.initials: J
authors.lastname: Lu
authors.forename: César
authors.initials: C
authors.lastname: Nombela-Arrieta
authors.forename: Jia
authors.initials: J
authors.lastname: Zhong
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.forename: Gregory
authors.initials: G
authors.lastname: Pivarnik
authors.forename: Subhanjan
authors.initials: S
authors.lastname: Mondal
authors.forename: Li
authors.initials: L
authors.lastname: Chai
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Silberstein
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
mesh_terms: D050156:Adipogenesis; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism; D001854:Bone Marrow Cells / Q000201:enzymology / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D019070:Cell Lineage; D060833:Cellular Microenvironment; D005269:Femur / Q000378:metabolism / Q000473:pathology; D006410:Hematopoiesis; D000072181:Inositol Polyphosphate 5-Phosphatases; D047569:Laser Scanning Cytometry; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000201:enzymology / Q000473:pathology
chemical_list: D010744:Phosphoric Monoester Hydrolases; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; D000072181:Inositol Polyphosphate 5-Phosphatases