Safety and efficacy of long-shelf-life allogeneic adipose-derived mesenchymal stem cell line-derived platelet-like cells for refractory foot ulcers: A translational preclinical and phase 1/2a study.

INTRODUCTION: Refractory foot ulcers, characterized by prolonged healing and frequent recurrences, challenge existing therapies such as revascularization and compression, which typically fail to prevent amputation. We developed adipose-derived mesenchymal stem cell line-derived platelet-like cells (ASCL-PLCs) for refractory ulcers that are long-lasting and readily available. METHODS: A translational preclinical investigation and phase 1/2a first-in-human clinical study assessed the safety and efficacy of a novel allogeneic ASCL-PLC treatment for refractory foot ulcers. In the pre-clinical phase, ASCL-PLCs were cryopreserved for 9 months and then thawed to measure cytokine release after calcium chloride stimulation. The therapeutic efficacy was evaluated in a diabetic mouse wound model, comparing ASCL-PLC treatment with vehicle control. The clinical trial involved topically applying ASCL-PLCs (1.5 × 10(8) cells/cm(2)) to the ulcers of four patients (two ischemic, two venous) on days 0, 14, and 28, with safety and efficacy monitored based on adverse events, ulcer size reduction, epithelialization time, and pain score changes. RESULTS: ASCL-PLCs maintained considerable cytokine-releasing activity even after long-term cryopreservation. In the diabetic mouse skin defect model, treatment with ASCL-PLCs substantially enhanced wound closure compared with the controls, demonstrating potent wound-healing capabilities. In the clinical trial, all patients exhibited notable ulcer size reduction without serious adverse events; three achieved epithelialization within 6 months, along with improvements in pain and quality of life without a negative impact on local blood flow. CONCLUSIONS: ASCL-PLCs are safe and a promising therapeutic option for refractory ulcers and can potentially reduce amputation rates, improve patient outcomes, and minimize the socioeconomic impact due to chronic wounds. Their long shelf life and cryopreservation stability make wound management practical and accessible. Moreover, their efficacy with simple topical application suggests a minimally invasive strategy suitable for outpatient care. Further large-scale trials are recommended.This study was registered with the Japan Registry of Clinical Trials (jRCT ID: jRCTa030200053; on June 18, 2020, https://jrct.mhlw.go.jp/en-latest-detail/jRCTa030200053).