Cell-Based Delivery of Interleukin-13 Directs Alternative Activation of Macrophages Resulting in Improved Functional Outcome after Spinal Cord Injury

Abstract

SummaryThe therapeutic effects of mesenchymal stem cell (MSC) transplantation following spinal cord injury (SCI) to date have been limited. Therefore, we aimed to enhance the immunomodulatory properties of MSCs via continuous secretion of the anti-inflammatory cytokine interleukin-13 (IL-13). By using MSCs as carriers of IL-13 (MSC/IL-13), we investigated their therapeutic potential, compared with non-engineered MSCs, in a mouse model of SCI. We show that transplanted MSC/IL-13 significantly improve functional recovery following SCI, and also decrease lesion size and demyelinated area by more than 40%. Further histological analyses in CX3CR1EGFP/+ CCR2RFP/+ transgenic mice indicated that MSC/IL-13 significantly decrease the number of resident microglia and increase the number of alternatively activated macrophages. In addition, the number of macrophage-axon contacts in MSC/IL-13-treated mice was decreased by 50%, suggesting a reduction in axonal dieback. Our data provide evidence that transplantation of MSC/IL-13 leads to improved functional and histopathological recovery in a mouse model of SCI.

Intracerebral delivery of the M2 polarizing cytokine interleukin 13 using mesenchymal stem cell implants in a model of temporal lobe epilepsy in mice

“…However, recent studies have described possible release of IL‐13 outside IL‐13 MSC grafts by showing beneficial effects in mouse models of cuprizone‐induced CNS demyelination and spinal cord injury. In these studies, the behavior of pathology‐associated microglia/macrophages was clearly altered (either being diminished or being M2 polarized), suggesting that IL‐13 may be involved in active CNS immunomodulation subsequently conferring neuroprotection . However, these potential mechanisms do not seem to be involved in this study, as no difference was observed between the hippocampal inflammatory responses in the control/vehicle and IL‐13 MSC groups.…”

“…Recent studies used intracerebral grafting of mesenchymal stem cells (MSCs) for in situ delivery of the M2 polarizing cytokine interleukin 13 (IL‐13). These studies found reduced microglia/macrophage immune response upon grafting IL‐13 MSCs, during cuprizone‐mediated central nervous system (CNS) inflammation and demyelination, as well as following spinal cord injury . In these specific models, a major inflammatory component precedes primary or secondary cellular injury, and the induction of M2 alternative activation of microglia/macrophages may thus be directly linked to reduced downstream microglia/macrophage cytotoxicity.…”

Combination of cuprizone and experimental autoimmune encephalomyelitis to study inflammatory brain lesion formation and progression

“…An additional cohort of Cup/EAE animals was used to investigate inflammatory brain lesions during chronic disease, 47 days after immunization. A second study utilized female CX 3 CR1 +/eGFP /CCR2 +/RFP reporter gene transgenic mice [C57BL/6 background; (Dooley et al, ; Le Blon et al, )] with green fluorescent microglia and red fluorescent infiltrating macrophages/monocytes under the same experimental conditions to discriminate brain‐resident microglia from infiltrating peripheral monocytes/macrophages.…”

“…All immunofluorescence analyses were performed according to previously described procedures (Dooley et al, ; Le Blon et al, ). Briefly, mice were transcardially perfused with a 0.9% NaCl solution followed by 4.0% PFA.…”

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

“…Using this approach, it appears as though these cell types may respond differently to interleukin-13, an M2inducing cytokine 30 ; in a model of spinal cord injury, IL-13 secretion from mesenchymal stem cells (MSCs) increased alternatively activated macrophages but reduced the overall number of microglia. 30 This suggests that not only are they difficult to distinguish, macrophages and microglia may also differentially influence the neuroinflammatory environment. As such, delineation of exclusive roles of these two immune cells in pathology have not been clearly defined to date, and also the mechanisms and therapeutic potential of cell polarization described later may be related to a combination effect of microglia and macrophages.…”