title: Fibrillin-1 microfibrils influence adult bone marrow hematopoiesis.
abstract: We have recently demonstrated that fibrillin-1 assemblies regulate the fate of skeletal stem cells (aka, mesenchymal stem cells [MSCs]) by modulating TGFβ activity within the microenvironment of adult bone marrow niches. Since MSCs can also influence hematopoietic stem cell (HSC) activities, here we investigated adult hematopoiesis in mice with Cre-mediated inactivation of the fibrillin-1 (Fbn1) gene in the mesenchyme of the forming limbs (Fbn1(Prx1-/-) mice). Analyses of 3-month-old Fbn1(Prx1-/-) mice revealed a statistically significant increase of circulating red blood cells, which a differentiation assay correlated with augmented erythropoiesis. This finding, together with evidence of fibrillin-1 deposition in erythroblastic niches, supported the notion that this extracellular matrix protein normally restricts differentiation of erythroid progenitors. Whereas flow cytometry measurements identified a decreased HSC frequency in mutant relative to wild type mice, no appreciable differences were noted with regard to the relative abundance and differentiation potential of myeloid progenitor cells. Together these findings implied that fibrillin-1 normally promotes HSC expansion but does not influence cell lineage commitment. Since local TGFβ hyperactivity has been associated with abnormal osteogenesis in Fbn1(Prx1-/-) mice, 1-month-old mutant and wild type animals were systemically treated for 8weeks with either a pan-TGF-β-neutralizing antibody or an antibody of the same IgG1 isotype. The distinct outcomes of these pharmacological interventions strongly suggest that fibrillin-1 differentially modulates TGFβ activity in HSC vs. erythroid niches.
authors.affiliation: Department of Pharmacology and Systems Therapeutics and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029.
authors.forename: Silvia
authors.initials: S
authors.lastname: Smaldone
authors.affiliation: Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029.
authors.forename: Carolina L
authors.initials: CL
authors.lastname: Bigarella
authors.affiliation: Department of Pharmacology and Systems Therapeutics and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029.
authors.forename: Maria
authors.initials: M
authors.lastname: Del Solar
authors.affiliation: Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029.
authors.forename: Saghi
authors.initials: S
authors.lastname: Ghaffari
authors.affiliation: Department of Pharmacology and Systems Therapeutics and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. Electronic address: francesco.ramirez@mssm.edu.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ramirez
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation; D000071838:Fibrillin-1 / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D055786:Gene Knockout Techniques; D006410:Hematopoiesis; D006801:Humans; D051379:Mice; D015398:Signal Transduction; D055153:Stem Cell Niche; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D016212:Transforming Growth Factor beta; C000605724:Fbn1 protein, mouse; D054392:Adipokines
keywords: Erythropoiesis; Fibrillin-1; Hematopoiesis; Marrow stem cells; TGFβ