Mesenchymal Stem Cells in Bone Regeneration

Abstract

Significance: Mesenchymal stem cells (MSCs) play a key role in fracture repair by differentiating to become bone-forming osteoblasts and cartilage-forming chondrocytes. Cartilage then serves as a template for additional bone formation through the process of endochondral ossification.

Recent advances: Endogenous MSCs that contribute to healing are primarily derived from the periosteum, endosteum, and marrow cavity, but also may be contributed from the overlying muscle or through systemic circulation, depending on the type of injury. A variety of growth factor signaling pathways, including BMP, Wnt, and Notch signaling, influence MSC proliferation and differentiation. These MSCs can be therapeutically manipulated to promote differentiation. Furthermore, MSCs can be harvested, cultivated, and delivered to promote bone healing.

Critical issues: Pharmacologically manipulating the number and differentiation capacity of endogenous MSCs is one potential therapeutic approach to improve healing; however, ideal agents to influence signaling pathways need to be developed and additional therapeutics that activate endogenous MSCs are needed. Whether isolated and purified, MSCs participate directly in the healing process or serve a bystander effect and indirectly influence healing is not well defined.

Future directions: Studies must focus on better understanding the regulation of endogenous MSCs durings fracture healing. This will reveal novel molecules and pathways to therapeutically target. Similarly, while animal models have demonstrated efficacy in the delivery of MSCs to promote healing, more research is needed to understand ideal donor cells, cultivation methods, and delivery before stem cell therapy approaches can be utilized to repair bone.

Kurt D. Hankenson, DVM, PhD

Figure 1.

Mesenchymal phase of fracture regeneration. Bones were harvested from mice 5 and 10 days postfracture. Callus tissue was decalcified, embedded in paraffin, sectioned, and stained with saffranin-o. Images were collected at 25× and 200× magnification to demonstrate the mesenchymal phase at day 5, and then how those cells differentiate to become bone-forming cells at day 10. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 2.

Endogenous sources of mesenchymal stem cells (MSCs) that contribute to fracture repair. MSCs that contribute to the fracture site are derived from the periosteum, endosteum, and the bone marrow. As well, MSCs present in the systemic circulation may also contribute to healing. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 3.

MSCs in fracture directly form osteoblasts and chondrocytes, but also may have indirect effects. MSCs are the cells that develop to become osteoblasts and chondrocytes. A variety of hypothesized and documented factors contribute to the differentiation process. These factors result in the modulation of transcription factors that are specific for the osteoblast and chondrocyte differentiation. MSCs at the fracture site may also contribute to bone healing through indirect effects, by producing cytokines, growth factors and regulating vascularization and modulating inflammation.

Figure 4.

Exogenous osteogenic, osteoinductive, and osteoconductive factors manipulating MSCs that could be used to promote fracture repair. Factors or MSCs could be delivered systemically through the circulation, or alternatively MSCs or factors can be directly delivered to a fracture site. Local delivery may involve direct injection or the loading of factors in scaffolds. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound