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 AsfahaC. 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

Research output: Contribution to journalArticlepeer-review

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).

Original languageEnglish (US)
Pages (from-to)269-284
Number of pages16
JournalCell
Volume160
Issue number1-2
DOIs
StatePublished - Jan 15 2015
Externally publishedYes

Bibliographical note

Funding Information:
Thank you to Dr. Liza Phillips. Thank you to all members of the Wang laboratory at Columbia University. Thank you to Professor David Callen, Dr. Miao Yang, and Dr. Laura Vrbanac at the University of Adelaide. Thank you to Dr. Lei Ding for his advice and assistance. Thank you to Dr. Grigori Enikolopov (Cold Spring Harbor Laboratory) and Dr. Rene Hen (Columbia University) for sharing their transgenic mice. Thank you to Dr. Victor Lin for his transgenic advice and to Dr. Brian Eyden for his advice regarding intestinal mesenchymal cells. We are grateful for the following funding: from the NIH to T.C.W. (NIH 5U54 CA126513), to S.M. (R01 RHL115145A), to F.Y.L. from the Robert Carroll and Jane Chace Carroll Laboratories and also the NIH (NIH AR056246 and EB006834), to A.K.R. from the American Cancer Society, and to D.L.W. from the NH&MRC and Menzies Foundation, Cancer Council SA’s Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health, Gastroenterological Society of Australia, the American Gastroenterological Association, the American Association for Cancer Research, the Royal Australasian College of Physicians, and the Ines Mandl Postdoctoral research fellowship Columbia University.

Publisher Copyright:
© 2015 Elsevier Inc.

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