Korean Circulation Journal 대한심장학회지 순환기 Lee SY, et al. Korean Circ J. 2020 Oct;51:e15. https://doi.org/10.4070/kcj.2020.0303

Scleroderma is an autoimmune disease caused by the abnormal regulation of extracellular matrix synthesis and is activated by non-regulated inflammatory cells and cytokines. Echinochrome A (EchA), a natural pigment isolated from sea urchins, has been demonstrated to have antioxidant activities and beneficial effects in various disease models. The present study demonstrates for the first time that EchA treatment alleviates bleomycin-induced scleroderma by normalizing dermal thickness and suppressing collagen deposition in vivo. EchA treatment reduces the number of activated myofibroblasts expressing α-SMA, vimentin, and phosphorylated Smad3 in bleomycin-induced scleroderma. In addition, it decreased the number of macrophages, including M1 and M2 types in the affected skin, suggesting the induction of an anti-inflammatory effect. Furthermore, EchA treatment markedly attenuated serum levels of inflammatory cytokines, such as tumor necrosis factor-α and interferon-γ, in a murine scleroderma model. Taken together, these results suggest that EchA is highly useful for the treatment of scleroderma, exerting anti-fibrosis and anti-inflammatory effects.

Hexapeptide WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met), a ligand of formyl peptide receptor 2, exhibits anti-inflammatory and angiogenic properties in disease models. However, the therapeutic effects of WKYMVm on hepatic fibrosis have not been evaluated to date. Therefore, we investigated whether WKYMVm exerts antifibrotic effects and induces vascular regeneration in a rat model of bile duct ligation (BDL). The antifibrotic and angiogenic effects of WKYMVm on liver regeneration in the BDL rat model were analyzed using biochemical assays, qRT-PCR, western blotting, immunofluorescence, and immunohistochemistry. To determine the effects of WKYMVm on hepatic fibrosis and angiogenesis in vitro, we measured the expression levels of fibrotic factors in hepatic stellate cells (HSCs) and angiogenic factors in human umbilical vein endothelial cells (HUVECs). WKYMVm attenuated the expression of collagen type I (Col I) and α-smooth muscle actin (α-SMA) and significantly increased the levels of angiogenetic factors in the BDL model (p < 0.05). WKYMVm reduced fibrotic marker expression in transforming growth factor (TGF)-β-induced HSCs and promoted angiogenic activity through tube formation in 5-Fluorouracil (FU)-treated HUVECs (p < 0.05). Also, WKYMVm administration enhanced hepatocyte proliferation in BDL rats (p < 0.05). The WKYMVm alleviates hepatic fibrosis by inhibiting HSC activation and promotes hepatic regeneration via vascular remodeling. These data suggest that the WKYMVm may be a new therapeutic agent for liver fibrosis.

Changes in the structure and function of blood vessels are important factors that play a primary role in regeneration of injured organs. WKYMVm has been reported as a therapeutic factor that promotes the migration and proliferation of angiogenic cells. Additionally, we previously demonstrated that placenta-derived mesenchymal stem cells (PD-MSCs) induce hepatic regeneration in hepatic failure via antifibrotic effects. Therefore, our objectives were to analyze the combination effect of PD-MSCs and WKYMVm in a rat model with bile duct ligation (BDL) and evaluate their therapeutic mechanism. To analyze the anti-fibrotic and angiogenic effects on liver regeneration, it was analyzed using ELISA, qRT-PCR, Western blot, immunofluorescence, and immunohistochemistry. Collagen accumulation was significantly decreased in PD-MSCs with the WKYMVm combination (Tx+WK) group compared with the nontransplantation (NTx) and PD-MSC-transplanted (Tx) group (p < 0.05). Furthermore, the combination of PD-MSCs with WKYMVm significantly promoted hepatic function by increasing hepatocyte proliferation and albumin as well as angiogenesis by activated FPR2 signaling (p < 0.05). The combination therapy of PD-MSCs with WKYMVm could be an efficient treatment in hepatic diseases via vascular remodeling. Therefore, the combination therapy of PD-MSCs with WKYMVm could be a new therapeutic strategy in degenerative medicine.

The application of light-emitting diode (LED)-dependent photobiomodulation (PBM) in promoting post-tendon injury healing has been recently reported. Despite establishing a theoretical basis for ligament restoration through PBM, identifying effective LED wavelength combinations and ensuring safety in animal models remain unresolved challenges. In our previous study, we demonstrated that combined irradiation at 630 nm and 880 nm promotes cell proliferation and migration, which are critical processes during the early stage of tendon healing in human-derived tendon fibroblasts. Based on this, we hypothesized that 630/880 nm LED-based PBM might promote rapid healing during the initial phase of tendon healing, and we aimed to analyze the results after PBM treatment in a murine model. Migration kinetics were analyzed at two specific wavelengths: 630 and 880 nm. The Achilles tendon in the hind limbs of Balb/c mice was severed by Achilles tendon transection. Subsequently, the mice were randomized into LED non-irradiation and LED irradiation groups. Mice with intact tendons were employed as healthy controls. The total number of mice was 13 for the healthy and injured groups and 14 for the LED-irradiated injured group, and the data presented in this manuscript were obtained from one representative experiment (n = 4–5 per group). The wounds were LED-irradiated for 20 min daily for two days. Histological properties, tendon healing mediators, and inflammatory mediators were screened on day 14. The roundness of the nuclei and fiber structure, indicating the degree of infiltrated inflammatory cells and severity of fiber fragmentation, respectively, were lower in the LED irradiation group than in the LED non-irradiation group. Immunohistochemical analysis depicted an increase in tenocytes (SCX⁺ cells) and recovery of wounds with reduced fibrosis (lower collagen 3 and TGF-β1) in the LED irradiation group during healing; conversely, the LED non-irradiation group exhibited tissue fibrosis. Overall, the ratio of M2 macrophages to total macrophages in the LED irradiation group was higher than that in the injured group. LED-based PBM in the Achilles tendon rupture murine model facilitated a rapid restoration of histological and immunochemical outcomes. These findings suggest that LED-based PBM presents remarkable potential as an adjunct therapeutic approach for tendon healing and warrants further research to standardize various parameters to advance and establish it as a reliable treatment regimen.

We present an integrated microelectrode array (MEA) platform for high‐precision electrophysiological characterization of patient‐derived 3D cardiac organoids (COs), enabling dynamic recordings from both healthy and Duchenne muscular dystrophy (DMD) “mini‐hearts.” A deformable MEA, fabricated by photolithographic patterning of support layers and microelectrodes, is conformally assembled onto a customized scoop‐slide well. The concave geometry enables passive self‐alignment of millimeter‐scale COs within a multichannel electrode array, allowing simultaneous extracellular field potential (EFP) recording and video‐based motion analysis. Using COs derived from human induced pluripotent stem cells of healthy donors and a DMD patient, we resolved region‐specific EFP waveforms, which were validated by calcium imaging. DMD COs exhibited severe arrhythmic firing and aberrant waveform morphologies, in contrast to the stable, isochronal rhythms of healthy controls. Single‐cell transcriptomic analysis revealed a pathological DMD signature marked by excessive extracellular matrix accumulation and disorganized cardiac architecture, contributing to conduction heterogeneity. Pharmacological challenge with the hERG blocker E‐4031 prolonged field potential duration in normal COs but triggered disorganized arrhythmogenic storms in DMD COs. By overcoming the limitations of rigid interfaces and ensuring structural preservation with stable impedance coupling, the presented platform provides a robust biointerface for disease phenotyping, drug screening, and mechanistic interrogation of 3D cardiac tissues.