Mesenchymal stromal cells for progressive multiple sclerosis: current evidence and translational challenges

Background Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by demyelinating lesions leading to cumulative and irreversible neurological damage. In the progressive form of MS (PMS), pathogenic mechanisms are multifaceted, involving both compartmentalized inflammation and neurodegeneration. Owing to their immunomodulatory and trophic properties, mesenchymal stromal cells (MSC) have emerged as a promising therapeutic strategy for this patient population. Objective To review the relevant immunomodulatory and neuroprotective mechanisms of MSC demonstrated in vitro , summarize preclinical and clinical evidence regarding MSC safety and efficacy in experimental autoimmune encephalomyelitis (EAE) murine model and in MS, and discuss key challenges hindering clinical translation. Main results MSC display combined immunomodulatory and neuroprotective properties that are particularly relevant in MS. They induce sustained immune reprogramming of T cells, B cells, and myeloid cells, through paracrine signaling, extracellular vesicle release, metabolic modulation, and efferocytosis of apoptotic cells. These effects are influenced by the local microenvironment, MSC tissue source, manufacturing processes, and route of administration. Beyond immune regulation, MSC promote CNS repair by secreting neurotrophic and angiogenic factors and through mitochondrial transfer. In chronic EAE models, MSC consistently reduce disease severity, mitigate CNS inflammation, and promote neuroprotection, with enhanced efficacy following intrathecal or intraventricular administration. Early-phase clinical trials in PMS have demonstrated a favorable safety profile but inconsistent efficacy, likely reflecting substantial heterogeneity in study design, cell products, dosing regimens, and administration routes. Nevertheless, emerging evidence suggests that repeated intrathecal administration and improved patient stratification may optimize therapeutic outcomes. Conclusion MSC-based therapies represent a potentially valuable avenue for PMS. However, their clinical benefit remains to be firmly established, pending well-designed trials addressing product standardization, optimized delivery approaches, and the use of robust, clinically meaningful endpoints.