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Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential
Daniel L Worthley1, Michael Churchill2, Jocelyn T Compton3
1Department 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.
Cell
|January 17, 2015
Summary
Researchers identified novel osteochondroreticular (OCR) stem cells in bone marrow, crucial for skeletal repair and development. These gremlin 1-expressing cells regenerate bone and cartilage, but not fat cells.
Area of Science:
- Stem cell biology
- Skeletal biology
- Connective tissue research
Background:
- Postnatal skeletal maintenance and repair rely on undefined stem cells.
- A proposed model involves perisinusoidal mesenchymal stem cells (MSCs) differentiating into various bone and marrow cell types, lacking experimental validation.
- The precise identity and function of skeletal stem cells remain a significant knowledge gap.
Purpose of the Study:
- To identify and characterize the specific stem cell population responsible for postnatal skeletal maintenance and repair.
- To investigate the role of gremlin 1 (Grem1) expression in defining skeletal stem cells.
- To determine the differentiation potential and anatomical location of these identified stem cells.
Main Methods:
- Utilized fate-mapping experiments to trace cell lineages within the bone marrow.
- Analyzed gene expression patterns, specifically focusing on the bone morphogenetic protein (BMP) antagonist gremlin 1 (Grem1).
- Examined the distribution and self-renewal capacity of Grem1-expressing cells in the bone marrow and intestine.
Main Results:
- Demonstrated that gremlin 1 expression defines a distinct population of osteochondroreticular (OCR) stem cells in the bone marrow.
- Showed that OCR stem cells possess self-renewal capabilities and generate osteoblasts, chondrocytes, and reticular marrow stromal cells, excluding adipocytes.
- Located OCR stem cells in the metaphysis of long bones, not the perisinusoidal space, and confirmed their necessity for bone development, remodeling, and fracture repair.
- Identified Grem1 expression in intestinal reticular stem cells (iRSCs), the origin of the periepithelial intestinal mesenchymal sheath.
Conclusions:
- Gremlin 1 expression serves as a marker for a unique population of connective tissue stem cells in both bone (OCR stem cells) and the intestine (iRSCs).
- OCR stem cells are critical for skeletal homeostasis, including development, ongoing remodeling, and the response to injury.
- The study refines our understanding of stem cell hierarchies and identifies specific cellular sources for distinct connective tissues.
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