title: Regionally Restricted Hox Function in Adult Bone Marrow Multipotent Mesenchymal Stem/Stromal Cells.
abstract: Posterior Hox genes (Hox9-13) are critical for patterning the limb skeleton along the proximodistal axis during embryonic development. Here we show that Hox11 paralogous genes, which developmentally pattern the zeugopod (radius/ulna and tibia/fibula), remain regionally expressed in the adult skeleton. Using Hoxa11EGFP reporter mice, we demonstrate expression exclusively in multipotent mesenchymal stromal cells (MSCs) in the bone marrow of the adult zeugopod. Hox-positive cells express PDGFRα and CD51, are marked by LepR-Cre, and exhibit colony-forming unit fibroblast activity and tri-lineage differentiation in vitro. Loss of Hox11 function leads to fracture repair defects, including reduced cartilage formation and delayed ossification. Hox mutant cells are defective in osteoblastic and chondrogenic differentiation in tri-lineage differentiation experiments, and these defects are zeugopod specific. In the stylopod (humerus and femur) and sternum, bone marrow MSCs express other regionally restricted Hox genes, and femur fractures heal normally in Hox11 mutants. Together, our data support regional Hox expression and function in skeletal MSCs.
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical Center, University of Michigan, 109 Zina Pitcher, 2053 BSRB, Ann Arbor, MI 48109-2200, USA.
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Rux
authors.affiliation: Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Song
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Ilea T
authors.initials: IT
authors.lastname: Swinehart
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical Center, University of Michigan, 109 Zina Pitcher, 2053 BSRB, Ann Arbor, MI 48109-2200, USA.
authors.forename: Kyriel M
authors.initials: KM
authors.lastname: Pineault
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Aleesa J
authors.initials: AJ
authors.lastname: Schlientz
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Kelsey G
authors.initials: KG
authors.lastname: Trulik
authors.affiliation: Department of Orthopedic Surgery, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Steve A
authors.initials: SA
authors.lastname: Goldstein
authors.affiliation: Department of Orthopedic Surgery, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Ken M
authors.initials: KM
authors.lastname: Kozloff
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical Center, University of Michigan, 109 Zina Pitcher, 2053 BSRB, Ann Arbor, MI 48109-2200, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lucas
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical Center, University of Michigan, 109 Zina Pitcher, 2053 BSRB, Ann Arbor, MI 48109-2200, USA; Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109-2200, USA; Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-2200, USA. Electronic address: dwellik@umich.edu.
authors.forename: Deneen M
authors.initials: DM
authors.lastname: Wellik
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001854:Bone Marrow Cells / Q000378:metabolism*; D002454:Cell Differentiation; D017102:Fracture Healing; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells; D008810:Mice, Inbred C57BL
chemical_list: D018398:Homeodomain Proteins; C487378:Tlx1 protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: Hox genes and limb development; mesenchymal stem cells; musculoskeletal system; skeletal repair; skeletal stem cells