Mesenchymal stromal/stem cell-based therapy for hemorrhagic stroke: mechanisms, clinical translation, and future perspectives

Abstract Hemorrhagic stroke encompasses anatomically and biologically distinct disorders, principally adult intracerebral hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (SAH); neonatal intraventricular hemorrhage (IVH) represents a separate developmental condition and should not be interpreted as an equivalent therapeutic population [1]. Current management addresses primary bleeding and acute physiological derangements but does not reliably arrest the evolving secondary injury response [2]. Despite disease-specific differences, partially shared mechanisms—including thrombin and complement activation, neuroinflammation, oxidative stress, blood–brain barrier (BBB) dysfunction, iron dysregulation and ferroptosis, and regulated cell death—provide a mechanistic rationale for mesenchymal stromal/stem cell (MSC)-based interventions. MSCs act predominantly through paracrine signaling, extracellular vesicles (EVs), immunomodulation, vascular support, and trophic repair rather than durable neuronal replacement [3]. Preclinical evidence is strongest for ICH and remains more limited for SAH, whereas clinical evidence is confined mainly to small early-phase studies in adult ICH and developmentally distinct neonatal IVH populations. These studies support feasibility and short-term tolerability, but efficacy and adult long-term safety remain unproven [4]. This review therefore evaluates MSC and MSC-EV mechanisms in a disease-stratified framework, distinguishes direct hemorrhagic-stroke evidence from cross-disease extrapolation, and outlines the manufacturing, potency, delivery, trial-design, and surveillance requirements needed for clinical translation.