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Improving Tendon Healing with Proregenerative Educated Macrophages

Review of “Extracellular Vesicle‐Educated Macrophages Promote Early Achilles Tendon Healing” from STEM CELLS by Stuart P. Atkinson

As the natural tendon healing process fails to regenerate the composition and mechanical properties of native tissue, new strategies to improve healing are currently under development. Researchers from the laboratories of Ray Vanderby and Peiman Hematti (University of Wisconsin‐Madison, Madison, Wisconsin, USA) recently demonstrated that ligament injury led to an increase in proinflammatory M1 macrophages before scar formation and tissue compromise [1]. However, the team also described how mesenchymal stem cells (MSCs) could “educate” macrophages via paracrine mechanisms to take on a more proregenerative anti‐inflammatory M2 phenotype [2]. Furthermore, educated macrophages enhanced mouse survival during lethal graft‐versus‐host disease and after radiation injury when compared with MSC or macrophage treatment alone [3], overall suggesting that proregenerative M2‐like educated macrophages may improve tendon healing.

Now, the team returns with a STEM CELLS article that reports their explorations into the ability of extracellular vesicles (EVs) derived from MSCs to educate macrophages to an M2 phenotype to act as a novel and efficient means to improve tendon healing [4]. Encouragingly, Chamberlain et al. now describe how treatment with M2‐like EV-educated macrophages enhances mechanical properties, reduces inflammation, and promotes earlier angiogenesis in a mouse Achilles tendon rupture model.

The authors made a broad comparison of M2‐like EV-educated macrophage treatment versus unaided tendon healing and treatments with MSCs, steady-state control macrophages, or EVs in a mouse Achilles tendon rupture model. Excitingly, the administration of EV-educated macrophages to the injured tendon supported an optimal regenerative response and increased in functionality by enhancing mechanical properties, reducing inflammation, and prompting earlier angiogenesis when compared to the other treatment modalities. Interestingly, while MSC‐derived EVs alone supported a more muted regenerative response, this treatment approach still stimulated an increase in the number of endothelial cells and a decrease in the M1/M2 macrophage ratio indicative of increased angiogenesis and reduced inflammation, respectively.

Given the safety and ease of generation of educated macrophages from patients own cells and off-the-shelf EVs, the authors hope that their new findings will represent a launch pad for the application of EV-educated macrophages in the treatment of conditions associated with inflammation and poor healing. The team also notes that EVs themselves may also play a significant therapeutic role in limiting ischemic injury and stimulating angiogenesis to enhance wound repair, although future research directions will include the delineating of the different mechanisms of EV- and EV-educated macrophage‐induced tendon healing.

For more on MSCs, macrophages, and extracellular vesicles, stay tuned to the Stem Cells Portal!

References

  1. Chamberlain CS, Crowley E, and Vanderby R, The spatio-temporal dynamics of ligament healing. Wound Repair and Regeneration 2009;17:206-15.
  2. Kim J and Hematti P, Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Experimental Hematology 2009;37:1445-53.
  3. Bouchlaka MN, Moffitt AB, Kim J, et al., Human Mesenchymal Stem Cell-Educated Macrophages Are a Distinct High IL-6-Producing Subset that Confer Protection in Graft-versus-Host-Disease and Radiation Injury Models. Biology of Blood and Marrow Transplantation 2017;23:897-905.
  4. Chamberlain CS, Clements AEB, Kink JA, et al., Extracellular Vesicle-Educated Macrophages Promote Early Achilles Tendon Healing. STEM CELLS 2019;37:652-662.