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Scarless Wound Healing Achieved Through Stem Cell-Derived Exosomes
The journey of the human body begins in infancy, often marked by flawless perfection. However, as time elapses and individuals grow, the passage of time become evident on their skin. From minor mosquito bites to major surgical incisions or burns, wounds of varying sizes leave enduring marks on the body. While some wounds heal swiftly, leaving no visible trace, others persist over the years, giving rise to unsightly scars.
Fibrotic scars on the skin typically arise from the healing of wounds in adults. These scars differ from normal skin due to the absence of skin appendages like hair follicles, sebaceous glands, and sweat glands. Moreover, they possess a dense extracellular matrix characterized by parallel fibers. Despite extensive research spanning decades, the achievement of scarless wound healing has remained an elusive goal.
Individuals grappling with scars often resort to scar removal products, often with suboptimal results. Is there a feasible way to facilitate wound healing without the consequential scar tissue formation?
In the realm of modern medicine, the pursuit of scarless wound healing has spurred researchers to explore innovative solutions that harness the body's innate regenerative capabilities. Placental stem cell-derived exosomes, a recent revelation in this field, have opened up promising avenues toward realizing this elusive objective.
A group of scientists has recently published a paper titled "Placental Stem Cells-Derived Exosomes Stimulate Cutaneous Wound Regeneration via Engrailed-1 Inhibition" in the journal Frontiers. Scar formation primarily hinges on the activity of Engrailed-1 (EN1) in fibroblast lineage. By inhibiting the activation of EN1, it is possible to promote wound regeneration and facilitate the reinstatement of skin appendages and microstructures. The study delved into the potential of mesenchymal stem cell (MSC) transplantation to mitigate scar formation.
The researchers uncovered that placental-derived MSCs exhibit a remarkable capacity to expedite wound healing. Notably, these stem cells not only accelerated the pace of wound closure but also enhanced the overall quality of wound healing. This improvement encompassed the regeneration of skin appendages such as hair follicles and sebaceous glands, a reduction in collagen I levels while augmenting collagen III, and the enhancement of collagen patterning (basket-weave structure) within healing skin. Additionally, treatment with placental-derived MSC promoted angiogenesis, underscoring the remarkable potential of wound regeneration through placental MSC-derived exosomes.
Exosomes have displayed functions exceeding initial expectations. Their influence extends beyond merely inhibiting scar tissue growth; they have also found a niche in both exosome diagnostics and therapeutics. These microvesicles hold promise as diagnostic and prognostic markers. The collection of exosomal markers from diverse samples like blood, urine, and saliva offers minimally invasive diagnostic techniques that alleviate patient discomfort.
As scientific progress continues, it is imperative to address ethical considerations and regulatory frameworks pertaining to exosome-based therapies. Functioning as natural carriers of signaling molecules, exosomes as drug carriers offer features such as biocompatibility, circulatory stability, and the ability to penetrate bio-barriers. This paves the way for the development of nanocarriers and cell-mediated drug delivery method. Furthermore, exosome-based drug formulations have demonstrated efficacy in addressing conditions spanning cancer, various infectious diseases, cardiovascular disorders, and neurodegenerative diseases.
In essence, the pursuit of scarless wound healing has yielded remarkable insights into the role of placental stem cell-derived exosomes. These diminutive vesicles not only propel skin regeneration but also harbor the potential to revolutionize diagnostics and therapeutics across multiple medical domains.
Decipher the Potential of IRF7 and CTSS as Therapeutic Targets for Skin Wound Healing
Introduction:
Adult skin wounds often result in the formation of regeneration-deficient scars, driven by an abnormal fibroproliferative response. This response, while beneficial in preventing long-term infections and nutrient loss at the injury site, presents a significant clinical challenge. In contrast, wound healing in embryos showcases lower inflammation levels and remarkable reconstructive capabilities.
On August 30, 2023, a collaborative effort brought forth a groundbreaking revelation in an online article titled "IRF7 and CTSS are pivotal for cutaneous wound healing and may serve as therapeutic targets", published in Signal Transduction and Targeted Therapy.
Interestingly, the fetus's ability to heal without scarring was found to be age-dependent. In mice, early gestation (embryonic day 16, E16) displayed near-normal healing post-injury, while late gestation (E18) exhibited marked fibrotic responses. The precise mechanisms underlying this transition remain largely enigmatic.
Critical Time Point at E18:
The authors' observations suggest that E18 represents a critical juncture in the shift from scarlessness to scar healing. 48 hours post-total skin excision surgery, E16 embryonic mice exhibited uniform wound healing, while E18 mice displayed strikingly distinct changes. In the E18 group, there was dense collagen remodeling and a notable accumulation of inflammatory cells. Collagen bundles in E18 wounds assumed scar-like structures, as indicated by higher FD values and lower L values compared to E16 wounds.
Crucial Factors in the Transition:
The study revealed a more pronounced accumulation of interleukin 6, activation of the NF-κB pathway, and enhanced osteoclast differentiation in the E18 group. These factors were implicated in the shift from an inflammatory response to late post-injury repair, leading to fibrosis and scarring. Notably, the Toll-like receptor (TLR) signaling pathway emerged prominently in the E18 group, suggesting a strong positive correlation between TLR pathway activation and late embryonic scarring. Cathepsin S (CTSS), a secreted protease involved in the TLR signaling pathway, was found to be significantly differentially expressed in the E18 group, while not in the E16 group. Immunohistochemical staining confirmed elevated CTSS expression in the E18 group at resection margins and residual sites, notably within fibroblasts and inflammatory cells.
The Impact of CTSS on Skin Fibroblasts:
The study further explored the effects of CTSS on human skin fibroblasts (HSFs). Transfection with a CTSS knockdown plasmid resulted in the downregulation of type I collagen, type III collagen, and fibronectin expression. Administering the CTSS inhibitor LY3000328 during the granulation and proliferation stages in a C57B1/6J model of proliferative scarring mice demonstrated remarkable results. Treatment with LY3000328 for ten consecutive days significantly reduced scar growth by 65.1% and reduced scar tissue thickness. Consequently, LY3000328 treatment diminished the cross-sectional area of scar tissue, effectively inhibiting myofibroblast activation and reducing scar formation.
IRF7 as a Key Regulator:
The study also revealed that IRF7 was a significant factor in upregulating CTSS. IRF7 was found to bind to the CTSS promoter in HSF cells, enhancing CTSS mRNA and protein expression. Interestingly, both IRF7 and CTSS exhibited upregulation in keloid, a pathological scar. This suggests that the overexpression of IRF7 and CTSS may play a pivotal role in keloid formation.
Conclusion:
This study highlights the transcriptional activation of CTSS in fibroblasts by IRF7 and underscores its potential as a therapeutic target for mitigating fibrosis. However, further investigations into their interactions with other cellular and molecular components during wound repair, including inflammatory monocytes, are warranted. Additionally, studies involving human proliferative scarring are essential, although they present challenges in acquiring clinical samples.
