Mesenchymal Stem Cells and Their Extracellular Vesicles: Therapeutic Mechanisms for Blood-Spinal Cord Barrier Repair Following Spinal Cord Injury

Abstract

Spinal cord injury (SCI) disrupts the blood-spinal cord barrier (BSCB) exacerbating damage by allowing harmful substances and immune cells to infiltrate spinal neural tissues from the vasculature. This leads to inflammation, oxidative stress, and impaired axonal regeneration. The BSCB, essential for maintaining spinal cord homeostasis, is structurally similar to the blood-brain barrier. Its restoration is a key therapeutic target for improving outcomes in SCI. Mesenchymal stromal/stem cells (MSCs) and their secreted extracellular vesicles (MSC-EVs) have gained attention for their regenerative, immunomodulatory, and anti-inflammatory properties in promoting BSCB repair. MSCs enhance BSCB integrity by improving endothelial-pericyte association, restoring tight junction proteins, and reducing inflammation. MSC-EVs, which deliver bioactive molecules, replicate many of MSCs' therapeutic effects, and offer a promising cell-free alternative. Preclinical studies have shown that both MSCs and MSC-EVs can reduce BSCB permeability, promote vascular stability, and support functional recovery. While MSC therapy is advancing in clinical trials, MSC-EV therapies require further optimization in terms of production, dosing, and delivery protocols. Despite these challenges, both therapeutic approaches represent significant potential for treating SCI by targeting BSCB repair and improving patient outcomes.

Keywords: blood–spinal cord barrier; extracellular vesicles; macrophages; mesenchymal stromal/stem cells; spinal cord injury; tight junction proteins.

Figure 1

Blood–Spinal Cord Barrier Disruption Following Spinal Cord Injury (SCI).(A) Schematic illustration depicting the cellular components of the blood–spinal cord barrier (BSCB) under normal conditions, with astrocytes, pericytes, and endothelial cells maintaining BSCB integrity. Following SCI, the barrier is disrupted, allowing infiltration of harmful substances such as pathogens, pro-inflammatory cells, and neurotoxic molecules into the spinal cord parenchyma. The area marked with an asterisk (*) in panel (A) is shown in an enlarged view in panel (B). (B) Tight junction breakdown is shown, where key proteins such as N-cadherin, occludin, and ZO-1 dissociate, resulting in increased BSCB permeability. This disruption leads to a loss of selective permeability, impaired nutrient and signaling molecule exchange, enlargement of blood vessels, neuroinflammation, and secondary injury processes that exacerbate neurotoxicity.

Figure 2

MSC and MSC-EV Mediated Repair of the Blood–Spinal Cord Barrier Post-SCI. (A). Intravenous (I.V) infusion of mesenchymal stem cells (MSCs) or their extracellular vesicles (MSC-EVs) plays a pivotal role in repairing the blood–spinal cord barrier (BSCB) following spinal cord injury (SCI). MSC-EVs specifically target M2 macrophages, enhancing their anti-inflammatory and reparative functions. This leads to the secretion of bioactive molecules that aid in endothelial cell stabilization and reduce inflammation at the injury site. The area marked with an asterisk (*) in panel (A) is shown in an enlarged view in panel (B). (B). MSC-EVs promote the restoration of the BSCB by upregulating tight junction proteins, such as occludin, ZO-1, and N-cadherin. These proteins help re-establish tight junction integrity, improving vascular stabilization and reducing the infiltration of harmful molecules into the spinal cord. Anti-inflammatory cytokines like TGF-β and IL-10, secreted by M2 macrophages, further support long-term BSCB repair and functional recovery.