期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：2
DOI：10.1073/pnas.2116865118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
This paper presents the synthetic artificial stem cell (SASC) system: a versatile therapy which provides the ability to tailor paracrine responses of different cells and provide a more potent regenerative effect for targeted tissues. Upon challenging the SASC system against an osteoarthritis model, we demonstrate that the factors combined tailored for chondrogenesis have a potent antiinflammatory and chondroprotective effect. This paper also demonstrates the in vivo capacity of SASC to attenuate proteoglycan depletion in the cartilage extracellular matrix while also improving biomechanical properties of the resulting cartilage. We report the first of many applications of the SASC system, which provides a promising step toward clinical translation of a minimally immunogenic stem cell with many commercial advantages over its biological counterpart.
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.
