In Aging, researchers have reported that deriving extracellular vesicles from mesenchymal stromal cells (MSCs) in fat tissue has beneficial effects in models of osteoarthritis.
Which source to use?
Earlier this month, we wrote about how small extracellular vesicles derived from embryonic cells (ESC-sEVs) alleviate arthritis in rodent models. While these researchers acknowledge the potential of ESC-based therapies, this study focuses on EVs from a different source: MSCs, specifically those derived from fat (adipose) tissue (ASCs). ASCs from ruminants’ antler tissues, just like EVs derived from other tissues, have been found to alleviate osteoarthritis in rat models [1] for the same fundamental reason: the alleviation of cellular senescence.
Similar results were found in a study of ASC-EVs in human cells derived from patients with advanced osteoarthritis [2], and a conditioned medium derived from ASCs was found to do similar things [3]. However, these researchers also realize that most studies, such as the one we covered earlier this month, are more focused on cells driven senescent by inflammation rather than DNA damage [4], and cells driven senescent by different origins can have different effects.
Positive effects against different senescence origins
This paper, therefore, conducts experiments on cartilage-generating chondrocytes that were driven senescent by DNA damage, which was inflicted through the administration of the toxin etoposide. As expected, these cells started exhibiting the senescence marker SA-β-gal along with the DNA damage marker γH2AX, with a trend towards an increase in the SASP.
Exposing these cells to ASC-EVs along with etoposide blunted the effects of the toxin. SASP markers, SA-β-gal expression, and even DNA damage as measured by γH2AX were all reduced. These changes were found to be at least partially due to a restoration of the balance between the metabolic buildup process of anabolism and the breakdown process of catabolism.
The researchers then turned to the more conventional method of inducing senescence through the inflammatory factor IL-1β. Compared to the etoposide-induced group, cells exposed to this factor did not exhibit DNA damage, although they had still had enlarged nuclear surfaces just as the etoposide group did. The SASP factors induced by IL-1β, however, were markedly increased compared to the etoposide group.
Fortunately, most of these factors were significantly downregulated when ASC-EVs had been previously introduced. The interleukins IL-6 and IL-8, two major SASP components, were affected, as were matrix metalloproteinases (MMPs). The researchers describe the effect as “senoprotective”, as it had prevented the cells from going senescent.
There was a very interesting difference between this study and the study from two weeks ago. In that study, the researchers reported that FOXO1 was upregulated, and FOXO3 was not; this study, on the other hand, reported the exact opposite. This suggests a distinction between the two EV sources and a possibility of combination treatments that use EVs derived from both sources.
Benefits in a mouse model
The researchers replicated their findings in a mouse model of induced osteoarthritis through collagen destruction with collagenase. Most notably, 24 days after the introduction of ASC-EVs, the treated group’s osteoarthritis score was nearly identical to that of the arthritis-free control group, and even after 42 days, the treatment still appeared to be effective in most mice. While not all of the many tested biomarkers went in the desired direction at 9 days or 14 days, an analysis of the expression of various genes led these researchers to conlude that ASC-EVs have a “therapeutic effect” in these mice.
This paper, like others before it, spends a considerable amount of time characterizing and diagnosing the target cells to which the treatment is targeted. With the various sources of EVs being shown to have effects in cells, this may be enough to bring these sorts of treatments into clinical trials, possibly if EVs from these sources are combined. However, it might also be of value to closely examine just what is in these tiny packages being sent from the donor cells and if it is possible to include or exclude any of their contents.
Literature
[1] Lei, J., Jiang, X., Li, W., Ren, J., Wang, D., Ji, Z., … & Wang, S. (2022). Exosomes from antler stem cells alleviate mesenchymal stem cell senescence and osteoarthritis. Protein & cell, 13(3), 220-226.
[2] Tofiño-Vian, M., Guillén, M. I., Pérez del Caz, M. D., Castejón, M. A., & Alcaraz, M. J. (2017). Extracellular vesicles from adipose‐derived mesenchymal stem cells downregulate senescence features in osteoarthritic osteoblasts. Oxidative Medicine and Cellular Longevity, 2017(1), 7197598.
[3] Platas, J., Guillén, M. I., Del Caz, M. D. P., Gomar, F., Castejón, M. A., Mirabet, V., & Alcaraz, M. J. (2016). Paracrine effects of human adipose-derived mesenchymal stem cells in inflammatory stress-induced senescence features of osteoarthritic chondrocytes. Aging (Albany NY), 8(8), 1703.
[4] Philipot, D., Guérit, D., Platano, D., Chuchana, P., Olivotto, E., Espinoza, F., … & Brondello, J. M. (2014). p16 INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis. Arthritis research & therapy, 16, 1-12.
