Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential

Daniel L Worthley; Michael Churchill; Jocelyn T Compton; Yagnesh Tailor; Meenakshi Rao; Yiling Si; Daniel Levin; Matthew G Schwartz; Aysu Uygur; Yoku Hayakawa; Stefanie Gross; Bernhard W Renz; Wanda Setlik; Ashley N Martinez; Xiaowei Chen; Saqib Nizami; Heon Goo Lee; H Paco Kang; Jon-Michael Caldwell; Samuel Asfaha; C Benedikt Westphalen; Trevor Graham; Guangchun Jin; Karan Nagar; Hongshan Wang; Mazen A Kheirbek; Alka Kolhe; Jared Carpenter; Mark Glaire; Abhinav Nair; Simon Renders; Nicholas Manieri; Sureshkumar Muthupalani; James G Fox; Maximilian Reichert; Andrew S Giraud; Robert F Schwabe; Jean-Phillipe Pradere; Katherine Walton; Ajay Prakash; Deborah Gumucio; Anil K Rustgi; Thaddeus S Stappenbeck; Richard A Friedman; Michael D Gershon; Peter Sims; Tracy Grikscheit; Francis Y Lee; Gerard Karsenty; Siddhartha Mukherjee; Timothy C Wang

doi:10.1016/j.cell.2014.11.042

Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential

Cell. 2015 Jan 15;160(1-2):269-84. doi: 10.1016/j.cell.2014.11.042.

Authors

Daniel L Worthley¹, Michael Churchill², Jocelyn T Compton³, Yagnesh Tailor², Meenakshi Rao⁴, Yiling Si², Daniel Levin⁵, Matthew G Schwartz⁶, Aysu Uygur⁶, Yoku Hayakawa², Stefanie Gross⁷, Bernhard W Renz², Wanda Setlik⁸, Ashley N Martinez³, Xiaowei Chen², Saqib Nizami³, Heon Goo Lee³, H Paco Kang³, Jon-Michael Caldwell³, Samuel Asfaha², C Benedikt Westphalen⁹, Trevor Graham¹⁰, Guangchun Jin², Karan Nagar², Hongshan Wang², Mazen A Kheirbek¹¹, Alka Kolhe², Jared Carpenter², Mark Glaire², Abhinav Nair², Simon Renders², Nicholas Manieri¹², Sureshkumar Muthupalani¹³, James G Fox¹³, Maximilian Reichert¹⁴, Andrew S Giraud¹⁵, Robert F Schwabe², Jean-Phillipe Pradere¹⁶, Katherine Walton¹⁷, Ajay Prakash¹⁷, Deborah Gumucio¹⁷, Anil K Rustgi¹⁴, Thaddeus S Stappenbeck¹², Richard A Friedman¹⁸, Michael D Gershon⁸, Peter Sims¹⁹, Tracy Grikscheit⁵, Francis Y Lee³, Gerard Karsenty⁷, Siddhartha Mukherjee²⁰, Timothy C Wang²¹

Affiliations

¹ 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.
² Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
³ Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY 10032, USA.
⁴ Department of Pediatrics, Columbia University, New York, NY 10032, USA.
⁵ Children's Hospital Los Angeles, Saban Research Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA.
⁶ Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
⁷ Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
⁸ Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
⁹ 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.
¹⁰ Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
¹¹ Department of Psychiatry, Columbia University, New York, NY 10032, USA.
¹² Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA.
¹³ Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁴ Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹⁵ Murdoch Children's Research Institute, Royal Children's Hospital, Vic., 3052, Australia.
¹⁶ 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.
¹⁷ Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁸ Herbert Irving Comprehensive Cancer Center Biomedical Informatics Shared Resource and Department of Biomedical Informatics, Columbia University, New York, NY 10032, USA.
¹⁹ Department of Systems Biology, Columbia University, NY, 10032, USA.
²⁰ Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA. Electronic address: sm3252@columbia.edu.
²¹ Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu.

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).

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Bone and Bones / cytology*
Cartilage / metabolism
Intercellular Signaling Peptides and Proteins / metabolism*
Intestine, Small / cytology*
Intestine, Small / metabolism
Mesenchymal Stem Cells / cytology*
Mesenchymal Stem Cells / metabolism
Mice
Mice, Inbred C57BL

Substances

Grem1 protein, mouse
Intercellular Signaling Peptides and Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding