title: Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential.
abstract: The stem cells that maintain and repair the postnatal skeleton remain undefined. One model suggests that perisinusoidal mesenchymal stem cells (MSCs) give rise to osteoblasts, chondrocytes, marrow stromal cells, and adipocytes, although the existence of these cells has not been proven through fate-mapping experiments. We demonstrate here that expression of the bone morphogenetic protein (BMP) antagonist gremlin 1 defines a population of osteochondroreticular (OCR) stem cells in the bone marrow. OCR stem cells self-renew and generate osteoblasts, chondrocytes, and reticular marrow stromal cells, but not adipocytes. OCR stem cells are concentrated within the metaphysis of long bones not in the perisinusoidal space and are needed for bone development, bone remodeling, and fracture repair. Grem1 expression also identifies intestinal reticular stem cells (iRSCs) that are cells of origin for the periepithelial intestinal mesenchymal sheath. Grem1 expression identifies distinct connective tissue stem cells in both the bone (OCR stem cells) and the intestine (iRSCs).
authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA; Department of Medicine, University of Adelaide, SA, 5005, Australia; Cancer theme, South Australian Health and Medical Research Institute, SA, 5001, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, Vic., 3052, Australia.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Pediatrics, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Children's Hospital Los Angeles, Saban Research Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA.
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authors.lastname: Levin
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
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authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY 10032, USA.
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authors.affiliation: Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY 10032, USA.
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authors.affiliation: Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY 10032, USA.
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authors.affiliation: Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA; Department of Internal Medicine III, University Hospital Munich, Ludwig-Maximilians-University Munich - Campus Groβhadern, Munich 81377, Germany.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA.
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authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA; Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC)- UMR1048, Toulouse 31432, France.
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authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
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authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
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authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA. Electronic address: sm3252@columbia.edu.
authors.forename: Siddhartha
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authors.affiliation: Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu.
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mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology*; D002356:Cartilage / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007421:Intestine, Small / Q000166:cytology* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016207:Cytokines
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C113178:Grem1 protein, mouse; D016207:Cytokines