Improved Wound Healing and Skin Regeneration Ability of 3,2′-Dihydroxyflavone-Treated Mesenchymal Stem Cell-Derived Extracellular Vesicles
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Se Hee Kim, Yeokyung Shin, Yujin Choi, Kyung Min Lim, Yeojin Jeong, Ahmed Abdal Dayem, Yoon-Joo Lee, Jongyub An, Kwonwoo Song, Soo Bin Jang, Ssang‐Goo Cho
A healing cell may not need to be placed into a wound to help it. This study suggests that tiny packages released by specially treated cells can calm inflammation and help damaged skin close faster.
Flavonoids enhance the self-renewal and differentiation potential of mesenchymal stem cells (MSCs) and have therapeutic activities, including regenerative, anti-oxidative, and anti-inflammatory effects. Recent studies have revealed that MSC-derived extracellular vesicles (MSC-EVs) have therapeutic effects on tissue regeneration and inflammation. To facilitate further research on the therapeutic potential of MSC-EVs derived from flavonoid-treated MSCs, we surveyed the production of EVs and their therapeutic applications in wound regeneration. MSCs treated with flavonoids enhanced EV production twofold compared with naïve MSCs. EVs produced by MSCs treated with flavonoids (Fla-EVs) displayed significant anti-inflammatory and wound-healing effects in vitro. The wound-healing capacity of EVs was mediated by the upregulation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling. Interestingly, the protein level of p-ERK under inhibition of MEK signals was maintained in Fla-EV-treated fibroblasts, suggesting that Fla-EVs have a higher therapeutic potential than naïve MSC-EVs (Cont-EVs) in wound healing. Moreover, the in vivo wound closure effect of the Fla-EVs showed significant improvement compared with that of the flavonoid-only treatment group and the Cont-EVs. This study provides a strategy for the efficient production of EVs with superior therapeutic potential using flavonoids.
Transcript
A healing cell may not need to be placed into a wound to help it. This study suggests that tiny packages released by specially treated cells can calm inflammation and help damaged skin close faster. Wound healing is a dynamic process involving inflammation, growth, and rebuilding.
Each phase is coordinated by immune cells and skin cells responding to signals from one another. Several studies have revealed that stem cells play pivotal roles in all phases of wound healing. The researchers focused on a flavonoid called three, two-prime-dihydroxyflavone, which had previously enhanced the growth and stem-like qualities of human reprogrammed cells.
They proposed that the compound could improve the growth of healing-support cells and activate cellular communication. The study tested whether treated cells could produce healing messages and more of them. To find a compound that increased cell growth, the researchers examined stem cells treated with various flavonoids.
Cells treated with 3,2′-dihydroxyflavone showed the highest growth among the flavonoids tested. The released packages reduced nitric oxide compared with the untreated EV group, and they also reduced several pro-inflammatory cytokine signals.
At one tested amount, packages from treated cells reduced nitric oxide about two times more than packages from untreated cells, and produced the strongest decreases in inflammatory signals. These results demonstrate that the treated-cell packages had a stronger anti-inflammatory effect than the untreated-cell packages, and that the effect increased with the amount given.
The key finding is that these tiny cell-made packages help skin-repair cells move into a wound, multiply, and activate a repair signal, while also speeding movement of surface skin cells. Blocking that signal weakens the response, linking it directly to faster wound closure.
The skin cells showed increased movement after treatment with the released packages, and wound closure was fastest in the group treated with packages from flavonoid-treated cells. Together, the results suggest that these packages help wounds by promoting the movement and growth of deeper skin-supporting cells and the movement of surface skin cells.
In mice, injecting the released packages significantly reduced wound size after five days, confirming a measurable healing effect in this model. In direct comparisons, the flavonoid-treated packages produced significantly greater wound closure than either the plant-derived compound alone or packages from untreated cells.
That comparison suggests that changing the cells first may produce a stronger healing treatment than giving the plant-derived compound or ordinary cell packages alone. The anti-inflammatory effects still need to be tested in living animals, because the proposed changes in inflammatory signals and immune-cell movement have not yet been confirmed inside a wound.
Mice heal wounds partly differently from humans, although the two species also share many healing features. More studies are needed before these packages can be judged as treatments for chronic wounds or other diseases. The study provides valuable insights into the potential of packages from flavonoid-treated cells as a wound-healing agent, but further studies are needed to understand how they work and address the study's limitations.
These results point toward possible new treatments for chronic wounds and inflammatory disorders, but further studies are needed before that promise can be realized. Treating stem cells with a plant-derived compound changed the healing messages they released.
Those messages reduced inflammation and improved wound closure in laboratory tests and mice, but human treatment remains a future question.
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