The synthetic artificial stem cell (SASC): Shifting the paradigm of cell therapy in regenerative engineering

Abstract

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.

Connection between Osteoarthritis and Nitric Oxide: From Pathophysiology to Therapeutic Target

“…Moreover, Shah et al used growth factors important to chondrogenesis and encapsulated recombinant proteins in poly (lactic-coglycolic acid) 85:15 (PLGA) to fabricate a synthetic artificial stem cell (SASC) system. After injecting SASC, it dramatically reduced the NO contents and gene expression levels of ADAMTS5 and the proteoglycan 4 (PRG4) genes in the OA rodent model, thereby demonstrating significant anti-inflammatory and chondroprotective effects [ 133 ].…”

Advanced Nanofiber-Based Scaffolds for Achilles Tendon Regenerative Engineering

“…Many studies have revealed that the therapeutic effect of non-tendon MSCs is mainly due to the ability of resident cells to be endowed by paracrine mechanisms or intercellular communication ( Daneshmandi et al, 2020 ; Chen et al, 2021b ; Shah et al, 2022 ). The MSCs regulate inflammation by secreting cytokines and stimulate AT tissue growth by secreting exosomes ( Shi et al, 2019 ; Yu et al, 2020 ).…”

Osteochondral regenerative engineering: challenges, state-of-the-art and translational perspectives

“…Most often, core–shell or layer-by-layer deposition of the biochemicals is used to avoid post-implantation ‘burst’ release. Recently, in the Laurencin group, a novel artificial stem cell mimicking system is developed (synthetic artificial stem cells) with the capability to deliver the target-specific secretomes to regulate chondrogenesis in the OA treatment [ 75 ]. Similarly, extracellular vesicles (EVs) released by mesenchymal stem/stromal cells, recently grabbed the attention in view of their regulatory capabilities in targeted bone and cartilage regeneration.…”