Transplantation of Mesenchymal Stem Cells Promotes an Alternative Pathway of Macrophage Activation and Functional Recovery after Spinal Cord Injury

Abstract

Mesenchymal stem cells (MSC) derived from bone marrow can potentially reduce the acute inflammatory response in spinal cord injury (SCI) and thus promote functional recovery. However, the precise mechanisms through which transplanted MSC attenuate inflammation after SCI are still unclear. The present study was designed to investigate the effects of MSC transplantation with a special focus on their effect on macrophage activation after SCI. Rats were subjected to T9-T10 SCI by contusion, then treated 3 days later with transplantation of 1.0 · 10 6 PKH26-labeled MSC into the contusion epicenter. The transplanted MSC migrated within the injured spinal cord without differentiating into glial or neuronal elements. MSC transplantation was associated with marked changes in the SCI environment, with significant increases in IL-4 and IL-13 levels, and reductions in TNF-a and IL-6 levels. This was associated simultaneously with increased numbers of alternatively activated macrophages (M2 phenotype: arginase-1-or CD206-positive), and decreased numbers of classically activated macrophages (M1 phenotype: iNOS-or CD16/32-positive). These changes were associated with functional locomotion recovery in the MSC-transplanted group, which correlated with preserved axons, less scar tissue formation, and increased myelin sparing. Our results suggested that acute transplantation of MSC after SCI modified the inflammatory environment by shifting the macrophage phenotype from M1 to M2, and that this may reduce the effects of the inhibitory scar tissue in the subacute/chronic phase after injury to provide a permissive environment for axonal extension and functional recovery.

Effect of Bone Marrow-derived Mesenchymal Stem Cells on Changes of Serum Levels of TNF-α and Locomotor Function after Spinal Cord Injury in Mice

“…All these events are correlated with a signi cant recovery of locomotor function in mice SCI (Nakajima et al, 2012). Although, PGE2 might be an intriguing candidate factor to be released by MSCs after cell-to-cell contact.…”

Stem cells for spine surgery

“…All of these studies reported that transplanted MSCs operate mainly through the creation of a favorable microenvironment by means of the secretion of a variety of neurotrophic factors [107][108][109][110][111] . However, the in vivo differentiation of MSCs into neuron-like cells has been documented to be inefficient [108][109][110] .…”

Transplantation of bone marrow mesenchymal stem cells pretreated with valproic acid in rats with an acute spinal cord injury

“…Pretreatment of BMSCs with VPA may enhance the therapeutic effects of BMSCs in SCI by increasing BMSC migration, which is closely related to SDF-1/ CXCR4. However, the mechanism of action of BMSCs in SCI therapy has yet to be fully elucidated (1)(2)(3). One possible mechanism is via the secretion of growth factors, like BDNF and GDNF, by BMSCs to reduce lesion volume and promote axonal regrowth of the injured spinal cord (26).…”

“…Mounting evidence has shown that mesenchymal stem cells derived from bone marrow (BMSCs) can improve recovery in SCI models by regulating host immunity, secreting neurotrophic factors, and differentiating into neurons (1)(2)(3). BMSC therapy has several advantages over therapy with other types of stem cells, including greater availability, less likelihood of immune rejection, and fewer ethical issues.…”