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.

Yi KH, et al. Yonsei Med J. 2023 Aug;64(8):511-517. https://doi.org/10.3349/ymj.2023.0124

Gwahn Woo Cheon, MD. The AESTHETICS 2025;5:27-32. https://doi.org/10.46738/Aesthetics.24.0001

Hyun Jin Cho, MD, Seung Min Oh, MD, MMBA, HyunJun Park, MD, Je Hyuk Lee, MD, Dae-Geun Song, MD, Geebum Kim, MD, PhD, MBA, Seon Oh Kim, MD, Gwahn Woo Cheon, MD, Sang Bong Lee, MD, Hoon-Young Kim, MD, Wan Jae Kim, MD. The AESTHETICS 2025;5:19-26. https://doi.org/10.46738/Aesthetics.25.0003

Platelet-rich plasma (PRP) is widely utilized for skin rejuvenation and tissue regeneration; however, its biological effects vary according to leukocyte content and molecular composition. We investigated the mechanism by which leukocyte-rich PRP (L-PRP) enhances extracellular matrix (ECM) regeneration in aged skin, focusing on the CCL1-CCR8/pyruvate kinase M2 (PKM2) signaling axis. First, we demonstrated that L-PRP contains significantly higher levels of CCL1 than platelet-poor plasma (PPP). In senescent human dermal fibroblasts, L-PRP increased CCL1-CCR8 interactions in a manner linked to enhanced formation and nuclear translocation of PKM2 dimers. This enhancement was accompanied by Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway activation and the upregulation of STAT3-dependent anti-apoptotic proteins (Bcl-2, Bcl-xL) and proliferative markers (Cyclin D1), resulting in increased fibroblast proliferation. Furthermore, L-PRP increased PKM2 tetramer levels, promoted PKM2-SMAD7 binding, and reduced SMAD7-mediated inhibition of transforming growth factor (TGF)-β signaling, leading to enhanced SMAD2/3 activation. These molecular events augmented the synthesis of collagen types I and III in senescent fibroblasts. In aged mice, intradermal L-PRP injections elicited dose-dependent increases in fibroblast proliferation, collagen fiber deposition, and skin elasticity. Nuclear PKM2 dimer/STAT3 signaling and PKM2 tetramer/TGF-β signaling were both more strongly activated in the L-PRP group. Our findings identify PKM2 as a central metabolic and signaling integrator linking immune-derived chemokines to fibroblast rejuvenation. This study provides mechanistic insights concerning how L-PRP promotes ECM regeneration in aged skin via coordinated regulation of fibroblast survival, proliferation, and collagen synthesis.

Injectable collagen biomaterials are used to modify the dermal extracellular matrix in aged skin; however, whether concentration-dependent rheological differences are associated with distinct fibroblast responses remain unclear. We compared 3% and 6% atelocollagen (AtCOL) and examined three mechanobiological programs: (i) integrin (ITG) α5β1–ERK–cyclin D1 signaling related to proliferation; (ii) ITGβ1–FAK–YAP signaling related to matrix synthesis; and (iii) ITGα11β1/Tensin-1–positive fibrillar adhesion related to collagen assembly. Under the tested oscillatory shear conditions, 6% AtCOL displayed higher storage modulus (G′), loss modulus (G″), and complex viscosity, together with a lower tan δ, than 3% AtCOL. In aged mouse skin, the 6% formulation was associated with greater increases in ITGα5, pERK1/2, cyclin D1, PCNA, pFAK, nuclear YAP, COL1A1, COL3A1, ITGα11β1/Tensin-1 co-expression signal, collagen type I/III ratio, collagen type I fiber bundle width, mature collagen content, dermal collagen density, and an instrument-derived skin elasticity index, while MMP1, MMP2, and MMP9 were reduced. In an H₂O₂-induced fibroblast senescence model, ITGβ1 knockdown attenuated AtCOL-associated proliferative, matrix-synthetic, and fibrillar-adhesion responses. Complementary ITGβ1 overexpression produced directionally concordant increases in ITGA11 expression, relative fibroblast proliferation, COL1A1, and COL3A1 and decreases in MMP1, MMP2, and MMP9. Collectively, these findings are consistent with a concentration-dependent, ITGβ1-centered mechanotransduction model linking fibroblast proliferation, matrix synthesis, and collagen assembly within a single AtCOL system.