Quiescence Recovers Adipose Tissue-Derived Stromal Cells from Senescence-Associated Secretory Phenotype, Leading to Enhanced Angiogenesis and Diabetic Wound Healing

Although a number of studies have shown that mesenchymal stem cells (MSCs) promote diabetic wound healing, their clinical applications are still limited. One of the reasons is that MSCs exhibit a senescence-associated secretory phenotype (SASP) in diabetes, which results in attenuation of their anti-inflammatory functions. We previously reported that adipose tissue-derived stromal cells (ADSCs), one type of MSCs used in multiple clinical trials, are able to exhibit their anti-inflammatory functions when they become quiescent in gels with a stiffness mimicking that of adipose tissue. We also showed that transplants containing quiescent ADSCs enhanced diabetic wound healing more than those containing non-quiescent ADSCs. Here, we investigated the effect of inducing quiescence in ADSCs on their angiogenic functions in a high glucose environment both in vitro and in vivo. High glucose-induced attenuated migration and tubular formation of HUVECs, an endothelial cell line, were ameliorated more significantly by conditioned medium from quiescent ADSCs cultured under high glucose than by that from non-quiescent ADSCs cultured under high glucose. Furthermore, ADSCs cultured at a high glucose level in vitro enhanced angiogenesis and wound healing in STZ-induced diabetic mice similarly to ADSCs cultured at a normal glucose level in vitro, when they were made quiescent in gels and subcutaneously injected into the mice. These results suggest that quiescence restores ADSCs from SASP and enhances angiogenesis even under diabetic conditions, which may be crucial for MSC-based cell therapies against diabetic microangiopathy. Disclosure M.Funaki: Board Member; Mechanogenic, Inc. H.Ogawa: None. T.Oya: None. A.Hata: None. M.Yoshida: None. N.Miyamoto: None. T.Ikuta: None. Y.Uemura: None. M.Akizuki: None. A.Tangoku: None. H.Yumoto: None.