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

Ali, Idrish; Aertgeerts, Stephanie; Blon, Debbie Le; Bertoglio, Daniele; Hoornaert, Chloé; Ponsaerts, Peter; Dedeurwaerdere, Stefanie

doi:10.1111/epi.13743

Cited by 21 publications

(28 citation statements)

References 32 publications

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“…5D-F). Unfortunately, this corroborates many other attempts with genetically modified MSCs (49,63,65,67). Studies that saw an improvement typically saw a change in only one out of multiple assessments, or only looked at a single time point (63,64,66).…”

Section: Discussionsupporting

confidence: 74%

“…SOD2 overexpression demonstrated improved motor coordination at one timepoint tested after focal TBI (64). IL-13 overexpression promotes an M2-like phenotype, but it has only been observed to improve some functional assessments in an SCI model and failed to rescue function in stroke and epilepsy models (65)(66)(67). IL-10 overexpression from MSCs did not reduce TBI lesion volume or improve most functional assessments (47,49).…”

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confidence: 99%

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Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

Enam

Kader

Bodkin

et al. 2020

Preprint

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Appropriately modulating inflammation after traumatic brain injury (TBI) may prevent disabilities for the millions of those inflicted annually. In TBI, cellular mediators of inflammation, including macrophages and microglia, possess a range of phenotypes relevant for an immunomodulatory therapeutic approach. It is thought that early phenotypic modulation of these cells will have a cascading healing effect. In fact, an anti-inflammatory, "M2-like" macrophage phenotype after TBI has been associated with neurogenesis, axonal regeneration, and improved white matter integrity. There already exists clinical trials seeking an M2-like bias through mesenchymal stem/stromal cells (MSCs). However, MSCs do not endogenously synthesize key signals that induce robust M2-like phenotypes such as Interleukin-4 (IL-4). To enrich M2-like macrophages in a clinically relevant manner, we augmented MSCs to transiently express IL-4 via synthetic IL-4 mRNA. We observed that these IL-4 expressing MSCs indeed induce a robust M2like macrophage phenotype and promote anti-inflammatory gene expression in a modified TBI model of closed head injury. However, here we demonstrate that acute enrichment of M2-like macrophages did not translate to improved functional or histological outcomes. This suggests that an acute enrichment of M2like macrophages cannot solely orchestrate the neurogenesis, axonal regeneration, and improved WMI after diffuse TBI. To further understand whether dysfunctional pathways underlie the lack of therapeutic effect, we report transcriptomic analysis of injured and treated brains. Through this, we discovered that inflammation persists in spite of acute enrichment of M2-like macrophages in the brain. Last, we comment on our modified TBI model, behavioral studies, and propose that IL-4 expressing MSCs may also have relevance in other cavitary diseases or in improving biomaterial integration into tissues.

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Section: Discussionsupporting

confidence: 74%

mentioning

confidence: 99%

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

Enam

Kader

Bodkin

et al. 2020

Preprint

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“…Another study, by inducing SE with a single dose of KA at 10 mg/Kg demonstrated inconsistent chronic epilepsy development, exemplified by only 26% of animals exhibiting >4 seizures/day and the remaining 76% displaying ~0.5 SRS/day [40]. Moreover, many post-SE prototypes have been employed previously in therapeutic efficacy studies once the occurrence of one or a few SRS was recorded [80][81][82][83]. Such investigations are valuable for ascertaining the beneficial effects of promising therapeutic compounds or biologics with an early intervention approach (i.e., application of therapy occurring immediately after the diagnosis of epilepsy or when the epileptogenic processes are still evolving).…”

Section: Discussionmentioning

confidence: 99%

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

Upadhya¹,

Kodali²,

Gitaí³

et al. 2019

Aging and disease

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Many animal prototypes illustrating the various attributes of human temporal lobe epilepsy (TLE) are available. These models have been invaluable for comprehending multiple epileptogenic processes, modifications in electrophysiological properties, neuronal hyperexcitability, neurodegeneration, neural plasticity, and chronic neuroinflammation in TLE. Some models have also uncovered the efficacy of new antiepileptic drugs or biologics for alleviating epileptogenesis, cognitive impairments, or spontaneous recurrent seizures (SRS). Nonetheless, the suitability of these models for testing candidate therapeutics in conditions such as chronic TLE is debatable because of a lower frequency of SRS and an inconsistent pattern of SRS activity over days, weeks or months. An ideal prototype of chronic TLE for investigating novel therapeutics would need to display a large number of SRS with a dependable frequency and severity and related co-morbidities. This study presents a new kainic acid (KA) model of chronic TLE generated through induction of status epilepticus (SE) in 6-8 weeks old male F344 rats. A rigorous characterization in the chronic epilepsy period validated that the animal prototype mimicked the most salient features of robust chronic TLE. Animals displayed a constant frequency and intensity of SRS across weeks and months in the 5th and 6th month after SE, as well as cognitive and mood impairments. Moreover, SRS frequency displayed a rhythmic pattern with 24-hour periodicity and a consistently higher number of SRS in the daylight period. Besides, the model showed many neuropathological features of chronic TLE, which include a partial loss of inhibitory interneurons, reduced neurogenesis with persistent aberrant migration of newly born neurons, chronic neuroinflammation typified by hypertrophied astrocytes and rod-shaped microglia, and a significant aberrant mossy fiber sprouting in the hippocampus. This consistent chronic seizure model is ideal for investigating the efficacy of various antiepileptic drugs and biologics as well as understanding multiple pathophysiological mechanisms underlying chronic epilepsy.

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“…Various soluble factors secreted by MSCs, including IL-4 [50], IL-13 [51], prostaglandin E2 (PGE2) [52], and tumor necrosis factor-α-induced gene/protein 6 (TSG-6) [53], have been shown to play a critical role in modulating inflammatory processes and macrophage polarization towards the M2 phenotype in animal models of sepsis [54], acute kidney injury [17], experimental colitis [18], spinal cord injury [19], and skin wounds [1]. To determine the key factors responsible for macrophage polarization towards the M2 phenotype induced by DFSC-CM, we performed a protein array, which revealed that rDFSCs could release many secreted proteins, including immunomodulatory factors, growth factors, cytokines, chemokines and neurotrophic factors, thus providing useful information for future studies.…”

Section: Discussionmentioning

confidence: 99%

Dental Follicle Stem Cells Ameliorate Lipopolysaccharide-Induced Inflammation by Secreting TGF-β3 and TSP-1 to Elicit Macrophage M2 Polarization

Chen

Yang

Tian

et al. 2018

Cell Physiol Biochem

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Background/Aims: Increasing evidence has demonstrated the novel roles of mesenchymal stem cells (MSCs) in immunotherapy. However, difficulty in acquiring these cells and possible ethical issues limited their application. Recently, we have isolated a unique MSC population from dental follicles with potent stem cell-like properties. This study focused on the effects of dental follicle stem cells (DFSCs) on macrophage activation and polarization to determine their role in immunomodulation and to test if DFSCs are a promising cell source for MSC-based immunotherapy. Methods: Rat acute lung injury (ALI) models induced by Lipopolysaccharide (LPS) were applied to test the immune-modulatory effects of DFSC/DFSC-CM in vivo. The pulmonary permeability was determined by the dry / wet weight ratios of the left upper lung lobe. The lung histopathological damage was graded on a 0 to 4+ scale. And the inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were tested by ELISA. Then we established LPS-induced inflamed macrophage models in vitro. Inflammatory cytokine production and polarization marker expression were measured by RT-qPCR, ELISA, western blot and flow cytometric analysis in macrophages following DFSC-CM treatment. The paracrine factors in DFSC-CM were revealed by a RayBiotech Protein Array. Thereafter, neutralization studies were performed to confirm the potential immune regulators in DFSC-CM. Results: The DFSC/DFSC-CM not only attenuated histopathological damage and pulmonary permeability, but also downregulated pro-inflammatory cytokines MCP-1, IL-1, IL-6 and TNF-α, and upregulated anti-inflammatory cytokine IL-10 in BALF. Immunofluorescence staining revealed the increased expression of macrophage M2 marker Arg-1. Further in vitro study revealed that macrophages switched to an anti-inflammatory M2 phenotype when co-cultured with DFSC-CM, characterized by suppressed production of pro-inflammatory cytokines MCP-1, IL-1, IL-6, TNF-α and M1-polarizing markers iNOS and CD86; and increased expression of the anti-inflammatory cytokine IL-10 and the M2-polarizing markers Arg-1 and CD163. A RayBiotech Protein Array revealed 42 differentially expressed (> 2-fold) paracrine factors in DFSC-CM compared with the serum-free Ham’s F-12K medium, among which TGF-β3 and Thrombospondin-1 (TSP-1) were upregulated by 18- and 105-fold, respectively. Neutralization studies confirmed the immunoregulatory roles of TGF-β3 and TSP-1 in macrophage activation and polarization. Conclusion: These results indicated that DFSCs can reprogram macrophages into the anti-inflammatory M2 phenotype, the paracrine factors TGF-β3 and TSP-1 may be one of the underlying mechanisms. This study supports the hypothesis that DFSCs are promising for MSC-based immunotherapy.

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

Cited by 21 publications

References 32 publications

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

Dental Follicle Stem Cells Ameliorate Lipopolysaccharide-Induced Inflammation by Secreting TGF-β3 and TSP-1 to Elicit Macrophage M2 Polarization

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