You are here

| Mesenchymal Stem Cells

Osteocyte-derived Extracellular Vesicles – A Novel Approach to Bone Regeneration?

Review of “Human bone marrow stem/stromal cell osteogenesis is regulated via mechanically activated osteocyte-derived extracellular vesicles” from STEM CELLS Translational Medicine by Stuart P. Atkinson

The mechanosensitive osteocytes present in the bone tissue [1] secrete paracrine acting factors when placed under mechanical stress to regulate the recruitment, proliferation, and osteogenic differentiation of the mesenchymal stem cells (MSCs) required for bone formation or regeneration [2]. Recently, researchers led by David A. Hoey (Trinity College Dublin, Ireland) explored the signaling pathways connecting mechanically stimulated osteocytes and MSCs through a detailed analysis of osteocyte-secreted factors. 

Reporting recently in STEM CELLS Translational Medicine [3], Eichholz et al. now establish the general importance of extracellular vesicles [4] in driving human MSC recruitment and osteogenesis in response to osteocytes that have been mechanically stimulated by culture under conditions of fluid shear stress. Furthermore, the authors suggest that these findings may prompt the development of a safe and effective cell-free therapeutic approach to bone regeneration and repair for diseases such as osteoporosis [5, 6].

Initial analysis of MSCs cultured in osteocyte conditioned medium revealed that only the secretome released from osteocytes cultured under shear stress conditions significantly induced osteogenesis, thereby supporting the importance of mechanical loading in mediating osteocyte-to-MSC signaling. Interestingly, a proteomic evaluation of the factors secreted by osteocytes revealed the enrichment of proteins associated with extracellular vesicles/exosomes; however, osteocytes cultured under shear stress conditions secreted a greater degree of extracellular vesicle-related proteins than those cultured in static conditions, thereby suggesting a pivotal role for extracellular vesicles in signaling between mechanically stimulated osteocytes and MSCs.

In confirmation of this hypothesis, the fluorescent labeling of osteocyte‐derived extracellular vesicles established their efficient uptake by MSCs. Furthermore, while exposure to extracellular vesicles derived from osteocytes cultured under static conditions prompted a slight improvement in MSC recruitment and osteogenic potential, extracellular vesicles derived from osteocytes cultured under shear stress conditions induced a significantly higher pro-osteogenic effect, as exemplified by significantly increased MSC recruitment, elevated osteogenesis-related gene expression, and enhanced alkaline phosphatase activity.

Overall, the authors provide evidence for the mechanism regulating mechanically‐induced bone formation – stimulated osteocytes secrete extracellular vesicles that induce the recruitment of MSCs and increase their osteogenic potential. These findings also support the exploration of extracellular vesicles derived from mechanically stimulated osteocytes as a safe and effective cell-free therapeutic approach to the induction of bone regeneration and repair in diseases such as osteoporosis.

For more on how osteocyte-derived extracellular vesicles may represent a novel approach to bone regeneration, stay tuned to the Stem Cells Portal!

References

  1. Dallas SL, Prideaux M, and Bonewald LF, The Osteocyte: An Endocrine Cell … and More. Endocrine Reviews 2013;34:658-690.
  2. Bonewald LF, The amazing osteocyte. Journal of Bone and Mineral Research 2011;26:229-238.
  3. Eichholz KF, Woods I, Riffault M, et al., Human bone marrow stem/stromal cell osteogenesis is regulated via mechanically activated osteocyte-derived extracellular vesicles. STEM CELLS Translational Medicine 2020;9:1431-1447.
  4. Yáñez-Mó M, Siljander PRM, Andreu Z, et al., Biological properties of extracellular vesicles and their physiological functions. Journal of Extracellular Vesicles 2015;4:27066.
  5. Bonewald LF, Osteocyte biology: its implications for osteoporosis. Journal of Musculoskeletal & Neuronal Interactions 2004;4:101-4.
  6. Qiu S, Rao DS, Palnitkar S, et al., Reduced Iliac Cancellous Osteocyte Density in Patients With Osteoporotic Vertebral Fracture. Journal of Bone and Mineral Research 2003;18:1657-1663.