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Abstract：
Poly-D,L-lactic acid (PDLLA) filler corrects soft tissue volume loss by increasing collagen synthesis in the dermis; however, the mechanism is not fully understood. Adipose-derived stem cells (ASCs) are known to attenuate the decrease in fibroblast collagen synthesis that occurs during aging, and nuclear factor (erythroid-derived 2)-like-2 factor (NRF2) increases ASCs survival by inducing M2 macrophage polarization and IL-10 expression. We evaluated the ability of PDLLA to induce collagen synthesis in fibroblasts by modulating macrophages and ASCs in a H2O2-induced cellular senescence model and aged animal skin. PDLLA increased M2 polarization and NRF2 and IL-10 expression in senescence-induced macrophages. Conditioned media from senescent macrophages treated with PDLLA (PDLLA-CMMΦ) reduced senescence and increased proliferation and expression of transforming growth factor-β (TGF-β) and fibroblast growth factor (FGF) 2 in senescence-induced ASCs. Conditioned media from senescent ASCs treated with PDLLA-CMMΦ (PDLLA-CMASCs) increased the expression of collagen 1a1 and collagen 3a1 and reduced the expression of NF-κB and MMP2/3/9 in senescence-induced fibroblasts. Injection of PDLLA in aged animal skin resulted in increased expression of NRF2, IL-10, collagen 1a1, and collagen 3a1 and increased ASCs proliferation in aged animal skin. These results suggest that PDLLA increases collagen synthesis by modulating macrophages to increase NRF2 expression, which stimulates ASCs proliferation and secretion of TGF-β and FGF2. This leads to increased collagen synthesis, which can attenuate aging-induced soft tissue volume loss.
摘要：
Poly-D,L-乳酸（PDLLA）填充剂通过增加真皮中的胶原蛋白合成来校正软组织体积损失；然而，机制尚未完全理解。已知脂肪来源的干细胞（ASC）可以减弱衰老过程中成纤维细胞胶原蛋白合成的减少，和核因子（红系衍生的2）样2因子（NRF2）通过诱导M2巨噬细胞极化和IL-10表达来增加ASC的存活。我们评估了PDLLA在H2O2诱导的细胞衰老模型和老化的动物皮肤中通过调节巨噬细胞和ASCs来诱导成纤维细胞中胶原蛋白合成的能力。PDLLA增加衰老诱导的巨噬细胞中的M2极化和NRF2和IL-10表达。用PDLLA（PDLLA-CMMΦ）处理的衰老巨噬细胞的条件培养基减少了衰老，并增加了衰老诱导的ASC中转化生长因子-β（TGF-β）和成纤维细胞生长因子（FGF）2的增殖和表达。用PDLLA-CMMΦ（PDLLA-CMASCs）处理的衰老ASCs的条件培养基增加了衰老诱导的成纤维细胞中胶原蛋白1a1和胶原蛋白3a1的表达，并降低了NF-κB和MMP2/3/9的表达。在老年动物皮肤中注射PDLLA导致NRF2，IL-10，胶原蛋白1a1和胶原蛋白3a1的表达增加，并增加了老年动物皮肤中ASCs的增殖。这些结果表明，PDLLA通过调节巨噬细胞增加NRF2表达来增加胶原蛋白合成，刺激ASC增殖和分泌TGF-β和FGF2。这导致胶原蛋白合成增加，可以减轻老化引起的软组织体积损失。
