Anti-Fibrotic and Regenerative Potential of Mesenchymal Stem Cell-Derived Exosomes in Cisplatin-Induced Kidney Injury

Öz

Cisplatin is a widely used chemotherapeutic agent with potent antitumor activity; however, its nephrotoxicity limits clinical use, affecting 30–40% of treated patients. This study aimed to investigate the effects of mesenchymal stem cell-derived exosomes on cisplatin-induced nephrotoxicity and fibrosis in rat kidney tissue. Rats were divided into Control, Cis, Exo, and Cis+Exo groups. Nephrotoxicity was induced by a single dose Cis. Exosomes were isolated using a commercial kit and characterized by nanoparticle tracking analysis. Histopathological evaluations were performed Hematoxylin&Eosin and Periodic Acid-Schiff. Fibrosis markers were assessed by immunohistochemistry. Statistical analyses were conducted using one-way ANOVA and Kruskal-Wallis tests with Bonferroni and Dunn’s post-hoc tests, considering p<0.05 as statistically significant. In the Cis group, significant tubular degeneration, necrosis, and fibrosis were observed compared to the Control group. TGF-β1, α-SMA, and TLR-4 expressions were markedly increased in the Cis group (p<0.001). Exo treatment significantly reduced the expression levels of these fibrosis markers compared to the Cis group (TGF-β1 and TLR-4, p<0.001; α-SMA, p<0.05). Histopathological analysis revealed that Exo administration mitigated nephrotoxic damage and supported tissue regeneration, with tissue architecture resembling that of the Control group. This study demonstrates that MSC-derived exosomes alleviate not only acute cisplatin-induced injury but also the associated fibrotic response. A single dose of exosome treatment significantly modulated the fibrotic response and reduced oxidative stress-induced damage. These findings indicate that MSC-derived exosomes, known for their regenerative and tissue-repairing properties, also possess significant potential as antifibrotic therapeutic agents, highlighting the need for further research toward clinical applications.

Anahtar Kelimeler

• exosomes
• fibrosis
• mesenchymal stem cell
• nephrotoxicity

Sisplatinle İndüklenen Böbrek Hasarında Mezankimal Kök Hücre Kökenli Eksozomların Anti-Fibrotik ve Rejeneratif Potansiyeli

Öz

Sisplatin, güçlü antitümöral aktiviteye sahip, yaygın olarak kullanılan bir kemoterapi ajanıdır; ancak nefrotoksisite oluşturması, klinik kullanımını sınırlamakta ve tedavi edilen hastaların %30–40'ında görülmektedir. Bu çalışma, mezankimal kök hücre kaynaklı eksozomların, sisplatin ile indüklenen nefrotoksisite ve fibrozis üzerindeki etkilerini sıçan böbrek dokusunda araştırmayı amaçlamıştır. Sıçanlar kontrol, Cis, Exo ve Cis+Exo olmak üzere dört gruba ayrıldı. Nefrotoksisite, tek doz sisplatin uygulanarak indüklendi. Eksozomlar ticari bir kit kullanılarak izole edildi ve nanoparçacık izleme analizi ile karakterize edildi. Histopatolojik değerlendirmeler Hematoksilen&Eozin, Periyodik Asit-Schiff ile yapıldı. Fibrozis belirteçleri immünohistokimyasal boyama ile değerlendirildi. İstatistiksel analizler, çoklu grup karşılaştırmaları için tek yönlü ANOVA ve Kruskal-Wallis testleri kullanılarak, Bonferroni ve Dunn post-hoc testleri ile gerçekleştirildi. p<0,05 değeri istatistiksel olarak anlamlı kabul edildi.Cis grubunda, kontrol grubuna kıyasla anlamlı düzeyde tübüler dejenerasyon, nekroz ve fibrozis gözlendi. Histopatolojik analizler, Exo uygulamasının nefrotoksik hasarı azalttığını ve doku rejenerasyonunu desteklediğini, doku mimarisinin Kontrol grubuna benzer hale geldiğini ortaya koydu. TGF-β1, α-SMA ve TLR-4 ekspresyonları Cis grubunda belirgin şekilde artmıştı (p<0,001). Exo tedavisi, bu fibrozis belirteçlerinin ekspresyon seviyelerini Cis grubuna göre anlamlı düzeyde azalttı (TGF-β1 ve TLR-4 için p<0,001; α-SMA için p<0,05). Bu çalışma, MSC kaynaklı eksozomların yalnızca akut sisplatin hasarını değil, aynı zamanda ilişkili fibrotik süreci de hafiflettiğini göstermektedir. Tek doz Exo tedavisi, fibrotik yanıtı anlamlı şekilde modüle etmiş ve oksidatif stres kaynaklı doku hasarını azaltmıştır. Bu bulgular, rejeneratif ve doku onarıcı etkileri iyi bilinen MSC kaynaklı eksozomların, aynı zamanda belirgin bir antifibrotik bir tedavi ajanı olma potansiyeline de sahip olduğunu göstermekte ve klinik uygulamalara yönelik ileri araştırmaların gerekliliğini ortaya koymaktadır.

Anahtar Kelimeler

• eksozom
• fibrozis
• mezenkimal kök hücre
• nefrotosisite
• sisplatin.

Kaynakça

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