Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health Center, Farmington, CT 06030.
Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, University of Connecticut Health, Farmington, CT 06030.
Proc Natl Acad Sci U S A. 2022 Jan 11;119(2). doi: 10.1073/pnas.2116865118.
Stem cells are of great interest in tissue regeneration due to their ability to modulate the local microenvironment by secreting bioactive factors (collectively, secretome). However, secretome delivery through conditioned media still requires time-consuming cell isolation and maintenance and also may contain factors antagonistic to targeted tissue regeneration. We have therefore engineered a synthetic artificial stem cell (SASC) system which mimics the paracrine effect of the stem cell secretome and provides tailorability of the composition for targeted tissue regeneration. We report the first of many applications of the SASC system we have formulated to treat osteoarthritis (OA). Choosing growth factors important to chondrogenesis and encapsulating respective recombinant proteins in poly (lactic-coglycolic acid) 85:15 (PLGA) we fabricated the SASC system. We compared the antiinflammatory and chondroprotective effects of SASC to that of adipose-derived stem cells (ADSCs) using in vitro interleukin 1B-induced and in vivo collagenase-induced osteoarthritis rodent models. We have designed SASC as an injectable therapy with controlled release of the formulated secretome. In vitro, SASC showed significant antiinflammatory and chondroprotective effects as seen by the up-regulation of SOX9 and reduction of nitric oxide, ADAMTS5, and PRG4 genes compared to ADSCs. In vivo, treatment with SASC and ADSCs significantly attenuated cartilage degeneration and improved the biomechanical properties of the articular cartilage in comparison to OA control. This SASC system demonstrates the feasibility of developing a completely synthetic, tailorable stem cell secretome which reinforces the possibility of developing a new therapeutic strategy that provides better control over targeted tissue engineering applications.
干细胞因其通过分泌生物活性因子（统称为分泌组）调节局部微环境的能力而在组织再生中受到广泛关注。然而，通过条件培养基进行分泌组传递仍然需要耗时的细胞分离和维持，并且可能含有与靶向组织再生拮抗的因子。因此，我们设计了一种合成人工干细胞 (SASC) 系统，该系统模拟了干细胞分泌组的旁分泌作用，并为靶向组织再生提供了组成的可定制性。我们报告了我们设计的 SASC 系统在治疗骨关节炎 (OA) 中的许多应用中的第一个。我们选择了对软骨生成很重要的生长因子，并将各自的重组蛋白封装在聚乳酸-乙醇酸 85:15 (PLGA) 中，制造了 SASC 系统。我们使用体外白细胞介素 1B 诱导和体内胶原酶诱导的 OA 啮齿动物模型比较了 SASC 与脂肪来源干细胞 (ADSCs) 的抗炎和软骨保护作用。我们将 SASC 设计为一种可注射的疗法，具有配方分泌组的控制释放。体外，与 ADSCs 相比，SASC 通过上调 SOX9 和降低一氧化氮、ADAMTS5 和 PRG4 基因显示出显著的抗炎和软骨保护作用。体内，与 OA 对照组相比，SASC 和 ADSCs 的治疗显著减轻了软骨退化并改善了关节软骨的生物力学特性。该 SASC 系统证明了开发完全合成、可定制的干细胞分泌组的可行性，这增加了开发新治疗策略的可能性，从而更好地控制靶向组织工程应用。
