Induced Pluripotent Stem Cell-Derived Conditioned Medium Attenuates Acute Kidney Injury by Downregulating the Oxidative Stress-Related Pathway in Ischemia–Reperfusion Rats

Abstract

Teratoma-like formation addresses a critical safety concern for the potential utility of induced pluripotent stem cells (iPSCs). Therefore, therapy utilizing iPSC-derived conditioned medium (iPSC-CM) for acute kidney injury (AKI) has attracted substantial interest. A recent study showed that iPSC-CM effectively alleviated ventilator-induced lung injury in rats. It prompts us to assess the therapeutic effects of iPSC-CM on ischemic AKI. First, we assessed the changes in renal function and tubular cell apoptosis by intraperitoneal administration of iPSC-CM to ischemia-reperfusion (I/R) rats. Second, we explored the oxidative stress-related pathway in the apoptosis of renal tubular cells subjected to hypoxia-reoxygenation (H/R). Administration of iPSC-CM significantly improved renal function and protected tubular cells against apoptosis in rats with I/R-AKI, and the optimal effect was observed at the 50-fold concentrated iPSC-CM. iPSC-CM also mitigated the H/R-induced apoptosis of NRK-52E cells in vitro. Reactive oxygen species (ROS) production was augmented in kidneys following I/R and in NRK-52E cells subjected to H/R. Meanwhile, expressions of phosphorylated p38 MAPK, TNF-a, and cleaved caspase 3 and NF-kB activity were consistently increased in vivo and in vitro. Following administration of iPSC-CM, ROS production was abolished, and inflammatory cytokine expression was significantly suppressed. Annexin V-propidium iodide flow cytometry and in situ TUNEL assay further showed that iPSC-CM markedly attenuated H/R-or I/R-induced tubular cell apoptosis. Intriguingly, treatment with iPSC-CM significantly improved the survival of rats with I/R-induced AKI. iPSC-CM represents a favorable source of stem cell-based therapy and may serve as a potential therapeutic strategy for kidney repair in ischemic AKI.

Controlled Delivery of Stem Cell-Derived Trophic Factors Accelerates Kidney Repair After Renal Ischemia-Reperfusion Injury in Rats

“…In another study using a rat model of CKD, van Koppen et al found that human embryonic MSC‐derived CM decreased the progression of CKD and improved tubular and glomerular injury . As in the case of the study , a high dose of CM injection (2 ml of 25 times concentrated of CM) was required to obtain an effective outcome . Intravenous injection of non‐concentrated CM (a total of 3.5 ml) did not restore renal function in a mouse I/R model .…”

“…C, D). Since the previous studies used various kidney injury models (e.g., AKI and CKD), CM sources (iPS‐CM and MSC), and administration routes (intraperitoneally and intravenously) , it makes direct comparisons very difficult. However, the dose that we used in our studies was much lower than that used previously, implying that effectively controlled CM delivery appears to be an important requisite for mitigating renal injuries.…”

Induced Pluripotent Stem Cell–conditioned Medium Suppressed Melanoma Tumorigenicity Through the Enhancement of Natural-Killer Cellular Immunity

“…3,6 Cancer had been viewed as a homogenous mass of rapidly proliferating cells, and therapeutics were designed to eliminate highly proliferative cells. However, recent studies have suggested that cancer cells are heterogenous with respect to proliferation and differentiation.…”

“…4,5 Intriguingly, our recent study further revealed that treatment with iPSC-conditioned medium increased the recipient survival effectively in rat ischemia/reperfusion-induced acute kidney injury models. 6 These findings highlighted that iPSC-conditioned medium represents a favorable source of stem cell-based therapy that carries minimal risk for teratoma formation in stem cell-based therapy. As the administration of iPSC-conditioned medium alone has been known to have minimal tumorigenic risk, it will be of high interest to explore whether iPSC-conditioned medium carries a tumor-suppressing effect that can hinder tumorigenesis and reverse tumor-induced immunosuppression in recipients.…”

Böbrek Kök Hücreleri

“…Böbrek hasarı oluşturulan deney hayvanlarına transplante edilen indüklenmiş pluripotent kök hücrelerle, renal hasarı gösteren belirteçlerin düzeyinin düştüğü, renal dokuların nekroz ve apoptozunun azaldığı ve renal tübül yapısının, hücre proliferasyonunun ve prorenal faktörlerin ifadesinin arttığı gösterilmiştir (49). Aynı zamanda, indüklenmiş pluripotent kök hücre uygulamasının renal fonksiyonları belirgin bir şekilde düzelttiği ve renal tübüler hücreleri apoptoza karşı koruduğu saptanmıştır (50). Sisplatin ile oluşturulan sıçan akut böbrek hastalığı modelinde, renal progenitör hücrelere farklılaştırılan indüklenmiş pluripotent kök hücrelerin hasarlı tübüle engrafte olduğu, renal fonksiyonları düzelttiği ve yapıyı onardığı gösterilmiştir (51).…”