PDF(Pubmed)
Abstract：
Poly L-lactic acid (PLLA) fillers stimulate collagen synthesis by activating various immune cells and fibroblasts. Piezo1, an ion channel, responds to mechanical stimuli, including changes in extracellular matrix stiffness, by mediating Ca2+ influx. Given that elevated intracellular Ca2+ levels trigger signaling pathways associated with fibroblast proliferation, Piezo1 is a pivotal regulator of collagen synthesis and tissue fibrosis. The aim of the present study was to investigate the impact of PLLA on dermal collagen synthesis by activating Piezo1 in both an H2O2-induced cellular senescence model in vitro and aged animal skin in vivo. PLLA elevated intracellular Ca2+ levels in senescent fibroblasts, which was attenuated by the Piezo1 inhibitor GsMTx4. Furthermore, PLLA treatment increased the expression of phosphorylated ERK1/2 to total ERK1/2 (pERK1/2/ERK1/2) and phosphorylated AKT to total AKT (pAKT/AKT), indicating enhanced pathway activation. This was accompanied by upregulation of cell cycle-regulating proteins (CDK4 and cyclin D1), promoting the proliferation of senescent fibroblasts. Additionally, PLLA promoted the expression of phosphorylated mTOR/S6K1/4EBP1, TGF-β, and Collagen I/III in senescent fibroblasts, with GsMTx4 treatment mitigating these effects. In aged skin, PLLA treatment similarly upregulated the expression of pERK1/2/ERK1/2, pAKT/AKT, CDK4, cyclin D1, mTOR/S6K1/4EBP1, TGF-β, and Collagen I/III. In summary, our findings suggest Piezo1\'s involvement in PLLA-induced collagen synthesis, mediated by heightened activation of cell proliferation signaling pathways such as pERK1/2/ERK1/2, pAKT/AKT, and phosphorylated mTOR/S6K1/4EBP1, underscoring the therapeutic potential of PLLA in tissue regeneration.
摘要：
聚L-乳酸(PLLA)填料通过激活各种免疫细胞和成纤维细胞来刺激胶原合成。Piezo1，离子通道，对机械刺激做出反应，包括细胞外基质硬度的变化，通过介导Ca2+流入。鉴于细胞内Ca2+水平升高触发与成纤维细胞增殖相关的信号通路，Piezo1是胶原蛋白合成和组织纤维化的关键调节剂。本研究的目的是在体外H2O2诱导的细胞衰老模型和体内衰老的动物皮肤中，通过激活Piezo1来研究PLLA对真皮胶原蛋白合成的影响。PLLA在衰老成纤维细胞中升高细胞内Ca2+水平，通过Piezo1抑制剂GsMTx4减弱。此外，PLLA处理增加磷酸化ERK1/2到总ERK1/2(pERK1/2/ERK1/2)和磷酸化AKT到总AKT(pAKT/AKT)的表达,表明途径激活增强。这伴随着细胞周期调节蛋白（CDK4和细胞周期蛋白D1）的上调，促进衰老成纤维细胞的增殖。此外,PLLA促进磷酸化mTOR/S6K1/4EBP1、TGF-β、和衰老成纤维细胞中的胶原蛋白I/III，用GsMTx4治疗减轻这些影响。在老化的皮肤，PLLA处理同样上调pERK1/2/ERK1/2、pAKT/AKT的表达,CDK4，细胞周期蛋白D1，mTOR/S6K1/4EBP1，TGF-β，和胶原蛋白I/III。总之,我们的发现表明Piezo1参与PLLA诱导的胶原合成，细胞增殖信号通路如pERK1/2/ERK1/2，pAKT/AKT，和磷酸化mTOR/S6K1/4EBP1，强调PLLA在组织再生中的治疗潜力。
