In the Journal of Nanobiotechnology, researchers have found that embedding microvesicles in a slow-release hydrogel may be an effective treatment for osteoarthritis.
A line of inquiry begins to bear fruit
Researchers have repeatedly found that the extracellular vesicles (EVs) released by stem cells, particularly mesenchymal stem cells (MSCs), are the main drivers behind the effectiveness of many stem cell-related approaches [1]. These intercellular messengers contain molecules with clear biological effects, such as microRNAs, proteins, and cytokines [2]. EVs are also considerably smaller than cells, small enough to penetrate deeply into otherwise impermeable tissues, such as cartilage [3].
We have repeatedly reported on the potential of EV-based treatments to alleviate age-related conditions, including cellular senescence. In this paper, the researchers developed a suite of EVs specifically to counteract senescent cells, with the goal of curing osteoarthritis caused by their accumulation in joints.
Special EVs and a special substrate
Because interferon gamma (IFN-γ) is a critical part of both causing senescence and causing senescent cells to die, and its presence affects how MSCs produce EVs [4], the researchers chose to cultivate both regular EVs (specifically microvesicles, MVs) and ones that were created after exposure to IFN-γ (iMVs).
However, EVs, including iMVs, are vulnerable and don’t last long in the human body. Therefore, researchers have investigated hydrogels as potential long-term treatments, as these substances can slowly release their contents over time [5]. Some hydrogels can be triggered to release their contents only in the presence of another substance or class of substances, such as reactive oxygen species (ROS) [6], which is the approach that these researchers took, delving deep into the specifics of their new material. They report that their hydrogel can continue to release MVs in the presence of ROS for nearly three weeks.
Effectiveness in cells and model rats
The researchers tested their new hydrogel substrate, complete with the incorporation of their MVs and iMVs, in the presence of cartilage-making cells (chondrocytes). This co-culturing was found to have no significant negative effects on the chrondrocytes. Instead, the presence of three key senescence markers, p16, p21, and p53, were substantially downregulated compared to a hydrogel-only control group in the presence of hydrogen peroxide.
The effects on energy transport were also analyzed. The membranes of mitochondria were improved after treatment with MVs and iMVs, although these vesicle types affected different respiratory chains at different levels. Hydrogel containing MVs or iMVs was found to significantly decrease the ROS in chondrocytes exposed to it. Additionally, exposure to iMVs was found to trigger mitochondrial fusion significantly beyond the effect of MVs.
A rat model was then employed to test this approach in vivo. This experiment consisted of eight weeks of induced arthritis followed by five weeks of testing. Both the empty hydrogel and treatment with iMVs alone were found to have some therapeutic benefit in this model. However, combining them had an enormous benefit: their cartilage had been nearly restored to the level of rats that had never had induced arthritis at all.
Just as in the cellular testing, this approach had been found to substantially reduce senescence markers. It also encouraged mitochondrial fusion and discouraged mitochondrial fission.
While this study was only conducted in cells and animal models, its results are promising and potentially groundbreaking. Combating arthritis by targeting cellular senescence has not always been met with success. If these rat results can be confirmed in human clinical trials, a vesicle and hydrogel-based approach may be more effective than senolytics
In summary, Hydrogel@iMVs effectively inhibits cartilage cell wear and delays the progression of OA by enhancing mitochondrial function and breaking the vicious cycle of senescence.
Literature
[1] Phinney, D. G., & Pittenger, M. F. (2017). Concise review: MSC-derived exosomes for cell-free therapy. Stem cells, 35(4), 851-858.
[2] Liu, X., Wei, Q., Sun, Z., Cui, S., Wan, X., Chu, Z., … & Wang, S. (2023). Small extracellular vesicles: Yields, functionalization and applications in diabetic wound management. Interdisciplinary Medicine, e20230019.
[3] Harrell, C. R., Jovicic, N., Djonov, V., Arsenijevic, N., & Volarevic, V. (2019). Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. Cells, 8(12), 1605.
[4] BaoB, Y. Z., LvC, X. L., WangB, Y. Z., & WangA, G. F. (2017). IFN-? induces senescence-like characteristics in mouse bone marrow mesenchymal stem cells. Adv. Clin. Exp. Med, 26, 201-206.
[5] Wang, J., Zhu, M., Hu, Y., Chen, R., Hao, Z., Wang, Y., & Li, J. (2023). Exosome-Hydrogel System in Bone Tissue Engineering: A Promising Therapeutic Strategy. Macromolecular Bioscience, 23(4), 2200496.
[6] Wu, Y., Wang, Y., Long, L., Hu, C., Kong, Q., & Wang, Y. (2022). A spatiotemporal release platform based on pH/ROS stimuli-responsive hydrogel in wound repairing. Journal of Controlled Release, 341, 147-165.
