title: Perivascular deletion of murine Rac reverses the ratio of marrow arterioles and sinusoid vessels and alters hematopoiesis in vivo.
abstract: Hematopoietic stem cells (HSCs) are localized within specialized microenvironments throughout the BM. Nestin-expressing (Nestin(+)) mesenchymal stromal cells (MSCs) are important in the perivascular space. Rac is critical for MSC cell shape in vitro, whereas its function in MSCs in vivo remains poorly characterized. We hypothesized that deletion of Rac in the Nestin(+) cells would perturb the perivascular space, altering HSC localization and hematopoiesis. Nestin-Cre-directed excision of Rac1 in Rac3(-/-) mice reduces Nestin(+) cells in the marrow. We observed a 2.7-fold decrease in homing of labeled wild-type hematopoietic cells into Rac1(Δ/Δ)Rac3(-/-) mice compared with control mice. Rac1(Δ/Δ)Rac3(-/-) mice demonstrated a marked decrease in arterioles and an increase in the number and volume of venous sinusoids in the marrow that was associated with a reduction in the numbers of immunophenotypically and functionally-defined long-term HSCs in the marrow, a decrease in colony-forming cells and a reduction in circulating progenitors. Rac-deleted animals demonstrated a significant increase in trabecular bone. These data demonstrate that Rac GTPases play an important role in the integrity of perivascular space. Increased trabecular bone and sinusoidal space and decreased arteriolar volume in this model were associated with decreased HSC, underscoring the complexity of regulation of hematopoiesis in the perivascular space.
authors.affiliation: Division of Hematology and Oncology and.
authors.forename: Marioara F
authors.initials: MF
authors.lastname: Ciuculescu
authors.affiliation: Division of Transfusion Medicine, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA.
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Division of Transfusion Medicine, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Canty
authors.affiliation: Division of Hematology and Oncology and.
authors.forename: Ronald
authors.initials: R
authors.lastname: Mathieu
authors.affiliation: Division of Transfusion Medicine, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA.
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Silberstein
authors.affiliation: Division of Hematology and Oncology and.
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001808:Blood Vessels; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D060833:Cellular Microenvironment; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D016130:Immunophenotyping; D051379:Mice; D018345:Mice, Knockout; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism; D019089:Stem Cell Factor / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D054377:Chemokine CXCL12; D064231:Nestin; D019089:Stem Cell Factor; D020744:rac GTP-Binding Proteins
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