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The epithelial-mesenchymal transition (EMT) process has emerged as a central regulator of embryonic development, tissue repair and tumor malignancy. In recent years, researchers have specifically focused on how mechanical signals drive the EMT program in epithelial cells. However, how epithelial cells specifically leverage mechanical force to control the EMT process remains unclear. Here, we show that the bona fide mechanically activated cation channel Piezo1 plays a critical role in the EMT. The Piezo1 is expressed in human primary epidermal keratinocytes (HEKs) and is responsible for the mechanical stretch-induced Ca2+ concentration. Inhibition of Piezo1 activation by the inhibitor GsMTx4 or by siRNA-mediated Piezo1 knockdown influenced the morphology and migration of HEKs. Moreover, Piezo1 activity also altered EMT-correlated markers expression in response to mechanical stretch. We propose that the mechanically activated cation channel Piezo1 is an important determinant of mechanical force-induced EMT in keratinocytes and might play similar roles in other epithelial cells.

Macrophages (Mφs) can be used as a part of cell-based cancer immunotherapy. However, they may be hampered by a failure to effectively and stably regulate their polarization state to enhance their t...

Obesity and its associated metabolic disorders such as diabetes, hepatic steatosis and chronic heart diseases are affecting billions of individuals. However there is no satisfactory drug to treat such diseases. In this study, we found that alisol A, a major active triterpene isolated from the Chinese traditional medicine Rhizoma Alismatis, could significantly attenuate high‐fat‐diet‐induced obesity. Our biochemical detection demonstrated that alisol A remarkably decreased lipid levels, alleviated glucose metabolism disorders and insulin resistance in high‐fat‐diet‐induced obese mice. We also found that alisol A reduced hepatic steatosis and improved liver function in the obese mice model.In addition, protein expression investigation revealed that alisol A had an active effect on AMPK/ACC/SREBP‐1c pathway. As suggested by the molecular docking study, such bioactivity of alisol A may result from its selective binding to the catalytic region of AMPK.Therefore, we believe that Alisol A could serve as a promising agent for treatment of obesity and its related metabolic diseases.

Adipose‐derived stem cells (ADSCs) are a subset of mesenchymal stem cells (MSCs), which have promised a vast therapeutic potential in tissue regeneration. Recent studies have demonstrated that combining stem cells with mechanical stretch may strengthen the efficacy of regenerative therapies. However, the exact influences of mechanical stretch on MSCs still remain inconclusive. In this study, human ADSCs (hADSCs) were applied cyclic stretch stimulation under an in vitro stretching model for designated duration. We found that mechanical stretch significantly promoted the proliferation, adhesion and migration of hADSCs, suppressing cellular apoptosis and increasing the production of pro‐healing cytokines. For differentiation of hADSCs, mechanical stretch inhibited adipogenesis, but enhanced osteogenesis. Long‐term stretch could promote ageing of hADSCs, but did not alter the cell size and typical immunophenotypic characteristics. Furthermore, we revealed that PI3K/AKT and MAPK pathways might participate in the effects of mechanical stretch on the biological characteristics of hADSCs. Taken together, mechanical stretch is an effective strategy for enhancing stem cell behaviour and regulating stem cell fate. The synergy between hADSCs and mechanical stretch would most likely facilitate tissue regeneration and promote the development of stem cell therapy.

Hypertrophic scar (HS) formation is a skin fibroproliferative disease that occurs following a cutaneous injury, leading to functional and cosmetic impairment. To date, few therapeutic treatments exhibit satisfactory outcomes. The mechanical force has been shown to be a key regulator of HS formation, but the underlying mechanism is not completely understood. The Piezo1 channel has been identified as a novel mechanically activated cation channel (MAC) and is reportedly capable of regulating force-mediated cellular biological behaviors. However, the mechanotransduction role of Piezo1 in HS formation has not been investigated. In this work, we found that Piezo1 was overexpressed in myofibroblasts of human and rat HS tissues. In vitro, cyclic mechanical stretch (CMS) increased Piezo1 expression and Piezo1-mediated calcium influx in human dermal fibroblasts (HDFs). In addition, Piezo1 activity promoted HDFs proliferation, motility, and differentiation in response to CMS. More importantly, intradermal injection of GsMTx4, a Piezo1-blocking peptide, protected rats from stretch-induced HS formation. Together, Piezo1 was shown to participate in HS formation and could be a novel target for the development of promising therapies for HS formation.

In the original article, Figs. 3b, 4a, c and 5d were published incorrectly. The correct version of the figures are provided in this correction.

It has been widely recognized that mechanical stretch can regulate the fate of stem cells (SCs). Previous research has shown that short-term mechanical stretch induces SC proliferation by activating the predominant transcription factor YAP, and YAP is a critical modulator in controlling epidermal proliferation. However, our study finds that after this phase, cell growth arrest appears, which is induced by long-term mechanical stretch. In the interfollicular epidermal SCs undergoing long-term mechanical stretch in vivo and in vitro, the level of H3K27me3 and its histone methyltransferase EZH2 are significantly elevated with suppressed expression of the target genes of YAP. EZH2 forms repressive H3K27me3 that suppresses gene transcription. Small-molecule inhibitor of EZH2 rescues significantly the cell growth arrest in interfollicular epidermal SCs induced by long-term mechanical stretch, thus promoting epidermal proliferation in vivo again. These findings reveal that there is an unexpected correlation between SC proliferation and the duration of mechanical stretch regulated by EZH2. This study of long-term mechanical stretch that induces cell growth arrest provides a strategy for clinical translation to promote skin regeneration.

Hypertrophic scar (HPS) presents as excessive extracellular matrix deposition and abnormal function of fibroblasts. However, there is no single satisfactory method to prevent HPS formation so far. Here, we found that honokiol (HKL), a natural compound isolated from Magnolia tree, had an inhibitory effect on HPS both in vitro and in vivo. Firstly, HKL could dose-dependently down-regulate the mRNA and protein levels of type I collagen, type III collagen, and α-smooth muscle actin (α-SMA) in hypertrophic scar-derived fibroblasts (HSFs). Secondly, HKL suppressed the proliferation, migration abilities of HSFs and inhibited HSFs activation to myofibroblasts, but had no effect on cell apoptosis. Besides, the in vivo rabbit ear scar model further affirmed the inhibitory effects of HKL on collagen deposition, proliferating cell nuclear antigen and α-SMA. Finally, Western blot results showed that HKL reduced the phosphorylation status of Smad2/3, as well as affected the protein levels of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase1. Taken together, this study demonstrated that HKL alleviated HPS by suppressing fibrosis-related molecules and inhibiting HSFs proliferation, migration as well as activation to myofibroblasts via Smad-dependent pathway. Therefore, HKL could be used as a potential agent for treating HPS and other fibrotic diseases.

The pathogenesis and therapy of hypertrophic scars (HS) have not yet been established. The aim of the present study was to investigate the potential effect of naringenin on HS and its underlying mechanisms. The mouse model of HS was prepared by a mechanical stretch device and then treated with naringenin at various concentrations. Histological studies were performed to evaluate scar hypertrophy by hematoxylin and eosin, as well as Masson's trichrome staining. The activation of HS fibroblasts was determined based on reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), western blotting and immunohistochemical staining. Following observing the retention of inflammation cells by immunohistochemistry, the cytokines, including tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β, IL‑6 and transforming growth factor (TGF)‑β1, mRNA and protein levels were quantitated by RT‑qPCR, ELISA and western blotting methods. As a result, naringenin significantly inhibited the formation of HS in a concentration‑dependent manner. In addition, naringenin inhibited fibroblast activation and inflammatory cell recruitment. In addition, mRNA and protein expression levels of TNF‑α, IL‑1β, IL‑6 and TGF‑β1 were downregulated following naringenin treatment. The current study highlighted a new pharmacological activity of naringenin on HS. The mechanism of action of naringenin was associated with the inhibition of fibroblast activation and local inflammation. These results suggested that naringenin may serve as a novel agent for treatment of HS.

Bone morphogenetic protein 2 (BMP2) has been used to induce bone regeneration by promoting osteogenic differentiation of bone marrow-derived mesenchymal stem cells (MSCs). However, its effect is attenuated in osteoporotic conditions by unknown mechanisms. In this study, we investigated the molecular mechanisms of reduced osteogenic effect of BMP2 in osteoporotic conditions. By interrogating the microarray data from osteoporosis patients, we revealed an upregulation of the epigenetic modifying protein lysine (K)-specific demethylase 5A (KDM5A) and decreased Runt-related transcription factor 2 (RUNX2) expression. Further studies were focused on the role of KDM5A in osteoporosis. We first established ovariectomized (OVX) mouse model and found that the BMP2-induced osteogenic differentiation of osteoporotic MSCs was impaired. The elevated level of KDM5A was confirmed in osteoporotic MSCs. Overexpression of KDM5A in normal MSCs inhibited BMP2-induced osteogenesis. Moreover, osteogenic differentiation of osteoporotic MSCs was restored by specific KDM5A short hairpin RNA or inhibitor. Furthermore, by chromatin immunoprecipitation assay we demonstrated that KDM5A functions as endogenous modulator of osteogenic differentiation by decreasing H3K4me3 levels on promoters of Runx2, depend on its histone methylation activity. More importantly, we found an inhibitory role of KDM5A in regulating bone formation in osteoporotic mice, and pretreatment with KDM5A inhibitor partly rescued the bone loss during osteoporosis. Our results show, for the first time, that KDM5A-mediated H3K4me3 modification participated in the etiology of osteoporosis and may provide new strategies to improve the clinical efficacy of BMP2 in osteoporotic conditions.

Mechanical stimulation and histone deacetylases (HDACs) have essential roles in regulating the osteogenic differentiation of bone marrow stromal cells (BMSCs) and bone formation. However, little is known regarding what regulates HDAC expression and therefore the osteogenic differentiation of BMSCs during osteogenesis. In this study, we investigated whether mechanical loading regulates HDAC expression directly and examined the role of HDACs in mechanical loading-triggered osteogenic differentiation and bone formation. We first studied the microarrays of samples from patients with osteoporosis and found that the NOTCH pathway and skeletal development gene sets were downregulated in the BMSCs of patients with osteoporosis. Then we demonstrated that mechanical stimuli can regulate osteogenesis and bone formation both in vivo and in vitro. NOTCH signaling was upregulated during cyclic mechanical stretch (CMS)-induced osteogenic differentiation, whereas HDAC1 protein expression was downregulated. The perturbation of HDAC1 expression also had a significant effect on matrix mineralization and JAG1-mediated Notch signaling, suggesting that HDAC1 acts as an endogenous attenuator of Notch signaling in the mechanotransduction of BMSCs. Chromatin immunoprecipitation (ChIP) assay results suggest that HDAC1 modulates the CMS-induced histone H3 acetylation level at the JAG1 promoter. More importantly, we found an inhibitory role of Hdac1 in regulating bone formation in response to hindlimb unloading in mice, and pretreatment with an HDAC1 inhibitor partly rescued the osteoporosis caused by mechanical unloading. Our results demonstrate, for the first time, that mechanical stimulation orchestrates genes expression involved in the osteogenic differentiation of BMSCs via the direct regulation of HDAC1, and the therapeutic inhibition of HDAC1 may be an efficient strategy for enhancing bone formation under mechanical stimulation.