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

495 Scopus citations


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
Pages (from-to)269-284
Number of pages16
Issue number1-2
StatePublished - 15 Jan 2015
Externally publishedYes


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