Spinal cord injury (SCI) is a devastating neurological condition that disrupts communication between the brain and body. The injury unfolds in two major phases. The primary injury occurs at the moment of trauma, such as a fracture or dislocation of the vertebrae, which directly damages neurons and axons. This mechanical disruption can immediately sever nerve pathways responsible for movement, sensation, and organ control.
The secondary injury phase develops over hours to months and significantly expands the initial damage. This phase includes vascular disruption, ionic imbalance, oxidative stress, and persistent inflammation. These processes injure surrounding healthy tissue and create an environment that inhibits axonal regeneration. Two dominant biological barriers emerge during this phase: chronic neuroinflammation and glial scar formation.
In this review, Pang et al. review the effects of inflammatory response and glial scar formation in spinal cord injury and repair.
Neuroinflammation After SCI: Cellular and Molecular Mechanisms
Inflammation is a natural response to injury. In the acute phase of SCI, inflammatory processes help remove cellular debris and initiate repair. However, when inflammation becomes excessive or prolonged, it can contribute to further neural degeneration.
One of the earliest pathological events is disruption of the blood–spinal cord barrier (BSCB). This normally protective barrier becomes permeable after injury, allowing peripheral immune cells to infiltrate the spinal cord. Damaged neural cells release danger signals known as damage-associated molecular patterns (DAMPs), which activate resident microglia and astrocytes. These cells release cytokines and chemokines that amplify immune cell recruitment and inflammatory signaling.
Neutrophils are the first circulating immune cells to arrive at the injury site, typically peaking within 24 hours. While they assist in debris clearance, they also release reactive oxygen species (ROS), proteolytic enzymes, and pro-inflammatory cytokines that can worsen tissue damage and demyelination.
Macrophages accumulate several days after injury. These cells exhibit functional plasticity and are broadly categorized into pro-inflammatory M1 and anti-inflammatory M2 phenotypes. M1 macrophages secrete cytokines such as TNF-α and IL-6, which promote tissue damage and inhibit axonal regeneration. M2 macrophages release anti-inflammatory mediators, such as IL-10 and TGF-β, which support tissue repair and remyelination. In SCI, the expected shift from M1 to M2 phenotypes is often incomplete, leading to persistent inflammatory injury.
Astrocytes also play a central role in neuroinflammation. After SCI, they become reactive and can adopt distinct phenotypes. A1-like astrocytes are associated with pro-inflammatory gene expression and synaptic damage, while A2-like astrocytes are linked to neuroprotection and growth factor production. The balance between these states influences recovery potential.
T lymphocytes further contribute to the inflammatory environment. Following SCI, the adaptive immune response often shifts toward pro-inflammatory Th1 and Th17 subsets, leading to increased cytokines such as IFN-γ and IL-17. Regulatory T cells (Tregs), which suppress inflammation, are comparatively reduced. This imbalance can exacerbate neuronal and myelin damage.
Therapeutic Modulation of Neuroinflammation
Current pharmacologic approaches to SCI-related inflammation are limited. High-dose steroids such as methylprednisolone have historically been used but remain controversial due to uncertain benefit and potential complications.
Mesenchymal stem cells (MSCs) have emerged as a promising strategy to modulate rather than completely suppress inflammation. MSCs can be isolated from bone marrow, adipose tissue, umbilical cord, placenta, and peripheral blood. Although initially believed to replace damaged neurons, current evidence suggests their primary benefit lies in immunomodulatory and paracrine signaling effects.
In preclinical SCI models, MSC transplantation has been associated with increased M2 macrophage polarization and decreased M1 dominance. These shifts are often accompanied by reduced levels of pro-inflammatory cytokines and increased levels of anti-inflammatory mediators, such as IL-10. MSCs also appear to influence astrocyte polarization, reducing harmful A1-like activation while promoting protective A2-like characteristics.
MSCs also regulate T cell responses. They inhibit T cell proliferation through soluble factors, including TGF-β, prostaglandin E2, nitric oxide, and indoleamine 2,3-dioxygenase. Importantly, MSCs promote shifts away from Th1/Th17 phenotypes and toward Tregs and Th2 subsets, contributing to a more repair-supportive immune profile.
Extracellular vesicles and exosomes derived from MSCs replicate many of these immunomodulatory effects. These vesicles carry proteins and genetic material that influence macrophage, astrocyte, and T cell behavior, suggesting that cell-free therapies may eventually complement or replace cell transplantation.
Timing of intervention appears critical. Some studies suggest MSC administration during the subacute phase—after the initial beneficial inflammatory burst—may optimize outcomes by reducing chronic inflammation while preserving early protective immune functions.
Glial Scar Formation: Cellular Composition and Functional Impact
Following SCI, a dense cellular structure known as the glial scar forms around the lesion core. Reactive astrocytes are the primary component, but microglia, NG2 glia, fibroblasts, infiltrating immune cells, and extracellular matrix proteins all contribute.
Astrocytes proliferate and hypertrophy, forming a tightly interwoven border around the injury site. This barrier physically isolates the damaged region. However, it also creates a structural obstacle to axonal regeneration.
A critical molecular component of the glial scar is chondroitin sulfate proteoglycans (CSPGs). These molecules strongly inhibit axonal growth and sprouting. Experimental reduction of CSPGs or enzymatic degradation using agents such as chondroitinase ABC has improved axonal regeneration and functional recovery in animal models.
CSPGs interact with neuronal receptors such as protein tyrosine phosphatase sigma (PTPσ), further blocking axonal extension. Targeting these pathways has demonstrated regenerative benefits in preclinical research.
Dual Role of the Glial Scar in SCI
Although traditionally viewed as a barrier to regeneration, the glial scar has a protective function in the early stages of SCI. Forming a containment boundary limits the spread of inflammatory cells, toxic molecules, and oxidative damage into surrounding healthy tissue. Studies have shown that complete prevention of astrocyte scar formation can worsen inflammation and tissue degeneration.
Therefore, the glial scar exhibits temporal duality. It is protective in the acute phase but inhibitory in the chronic phase. Effective therapeutic strategies must consider this dynamic role rather than simply attempting complete scar elimination.
MSC Regulation of Glial Scar Formation
MSCs influence glial scar dynamics by modulating astrocyte activity and extracellular matrix deposition. In animal models, MSC transplantation has been associated with reduced astrocyte activation and decreased CSPG accumulation in later stages of injury.
Certain MSC-based approaches incorporate biomaterials such as hydrogels or scaffolds to improve cell survival in the hostile injury environment. These combinations enhance sustained release of growth factors and anti-inflammatory cytokines, further supporting axonal regeneration.
Transforming growth factor beta (TGF-β) is a key driver of astrocyte proliferation and CSPG production through Smad signaling pathways. MSC transplantation has been shown to reduce TGF-β signaling activity, thereby limiting scar density. Some studies also report that MSCs may promote early protective astrocyte responses while attenuating chronic scar formation, suggesting stage-specific regulatory effects.
Clinical Translation and Ongoing Challenges
Clinical interest in MSC therapy for SCI is expanding, with multiple registered trials investigating intrathecal, intramedullary, and intravenous delivery methods. Early-phase studies generally report favorable safety profiles, with most adverse effects limited to mild or transient symptoms such as headache or injection-site discomfort.
However, definitive conclusions regarding efficacy remain limited by small sample sizes, patient heterogeneity, and variability in injury timing and severity. Larger randomized controlled trials are required to establish therapeutic benefit.
Some safety considerations also warrant attention. The cell source, manufacturing standards, culture duration, and genetic stability vary across laboratories, emphasizing the need for standardized protocols.
Therapeutic Implications and Future Directions
Spinal cord injury triggers a complex cascade of neuroinflammation and glial scar formation that collectively inhibit axonal regeneration and functional recovery. Inflammation plays a dual role, contributing to early debris clearance but driving secondary tissue damage when prolonged. The glial scar similarly protects in the acute phase while restricting regeneration in the chronic phase.
Mesenchymal stem cells represent a biologically rational strategy to modulate both neuroinflammation and scar formation. Rather than acting primarily as replacement neurons, MSCs exert immunoregulatory and paracrine effects that shift immune cell phenotypes, influence astrocyte activation, and reshape the injury microenvironment.
Preclinical evidence strongly supports these mechanisms, and early clinical studies suggest safety and feasibility. Ongoing research is focused on optimizing cell source, timing, delivery method, and long-term safety to determine whether MSC-based therapies can meaningfully improve outcomes for individuals living with spinal cord injury.
Source: Pang QM, Chen SY, Xu QJ, Fu SP, Yang YC, Zou WH, Zhang M, Liu J, Wan WH, Peng JC, Zhang T. Neuroinflammation and Scarring After Spinal Cord Injury: Therapeutic Roles of MSCs on Inflammation and Glial Scar. Front Immunol. 2021 Dec 2;12:751021. doi: 10.3389/fimmu.2021.751021. PMID: 34925326; PMCID: PMC8674561.