Abstract Background and aims Although intra-arterial thrombectomy has transformed acute ischemic stroke treatment, the gap between recanalization and tissue recovery remains unresolved. Human umbilical cord–derived mesenchymal stem cells (UMSCs) have demonstrated therapeutic potential. We conducted an open-label sequential pilot trial to evaluate the safety of combined intravenous and intra-arterial UMSC transplantation in acute ischemic stroke. Methods Patients aged ≥20 years with acute unilateral middle cerebral artery ischemic stroke, baseline National Institutes of Health Stroke Scale (NIHSS) scores of 8–20, and pre-stroke modified Rankin Scale (mRS) scores of 0–1 were enrolled. Patients with NIHSS changes ≥5 points during screening were excluded. Following regulatory-approved quality verification, UMSCs were administered intravenously within 24–36 hours of stroke onset, followed by catheter-guided intra-arterial delivery via the middle cerebral artery on Day 7. The primary endpoint was safety. Results Ten patients were enrolled between December 2020 and December 2025 (mean age 68.5 ± 8.1 years; mean baseline NIHSS 13.7 ± 3.7). No serious treatment-related adverse events occurred. Two patients developed transient renal dysfunction unrelated to UMSC therapy. One patient exhibited mild hemorrhagic transformation on routine follow-up MRI, considered possibly related to treatment. Significant improvements were observed at Day 90 in NIHSS (4.5 ± 4.9 vs. 13.7 ± 3.7, p 0.001), mRS (2.1 ± 1.5 vs. 3.8 ± 0.6, p 0.001), and Barthel Index (14.9 ± 3.7 vs. 2.7 ± 3.4, p 0.001). Conclusions Dual-route UMSCs therapy was safe and well tolerated, with signals of functional improvement following acute ischemic stroke. Larger randomized controlled trials are warranted. Conflict of interest Sheng-Ta Tsai: nothing to disclose; Yuh-Cherng Guo: nothing to disclose; Cheng-Li Lin: nothing to disclose; Hei-Tung Yip: nothing to disclose; Wei-Chun Wang: nothing to disclose; Kang-Hsu Lin: nothing to disclose; Wei-Laing Chen: nothing to disclose; Chon-Haw Tsai: nothing to disclose; Long-Bin Jeng is a shareholder of Ever Supreme Bio Technology; Woei-Cherng Shyu is a shareholder of Ever Supreme Bio Technology and an employee of both Ever Supreme Bio Technology and China Medical University Hospital.
Tsai et al. (2026) studied this question.