Quiescent adipose tissue-derived stromal cells in mechanically compliant hydrogel accelerate diabetic wound healing through enhanced functions and extended dwell time

Abstract

Despite the therapeutic potential of mesenchymal stem cells (MSC), there are few clinical applications. One of the reasons is that MSC administered by conventional methods quickly disappear from the recipient, which leads to insufficient efficacy. We previously reported that MSC become quiescent in hydrogel with stiffness mimicking that of bone marrow or adipose tissue. In this study, we investigated whether inducing quiescence in adipose tissue-derived stromal cells (ADSC), one type of MSC, may overcome such a weakness. ADSC became quiescent in biocompatible gel whose stiffness matched that of adipose tissue, even in the presence of tumor necrosis factor α and interferon γ to mimic an inflammatory environment in vitro. Quiescent ADSC exhibited enhanced anti-inflammatory functions and fibroblast migration in vitro, suggesting enhanced therapeutic functions of ADSC by quiescence. Subcutaneous transplantation of quiescent ADSC accelerated wound healing in diabetic mice, which can also be attributed to their extended dwell time at the transplanted site, without any pathological changes. Inducing quiescence in ADSC also led to elimination of accumulated reactive oxygen species. These results suggest that quiescent ADSC may enhance the efficacy of ADSC-based cell therapies to treat diabetic wound healing.