Back to Search
Start Over
Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells
- Source :
- Journal of Neuroinflammation, Vol 17, Iss 1, Pp 1-24 (2020), Journal of Neuroinflammation
- Publication Year :
- 2020
- Publisher :
- BMC, 2020.
-
Abstract
- BackgroundAppropriately 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 (WMI). There already exist 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).MethodsTo enrich M2-like macrophages in a clinically relevant manner, we augmented MSCs with synthetic IL-4 mRNA to transiently express IL-4. These IL-4 expressing MSCs (IL-4 MSCs) were characterized for expression and functionality and then delivered in a modified mouse TBI model of closed head injury. Groups were assessed for functional deficits and MR imaging. Brain tissue was analyzed through flow cytometry, multi-plex ELISA, qPCR, histology, and RNA sequencing.ResultsWe observed that IL-4 MSCs indeed induce a robust M2-like macrophage phenotype and promote anti-inflammatory gene expression after TBI. However, here we demonstrate that acute enrichment of M2-like macrophages did not translate to improved functional or histological outcomes, or improvements in WMI on MR imaging. 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 despite acute enrichment of M2-like macrophages in the brain.ConclusionThe results demonstrate that MSCs can be engineered to induce a stronger M2-like macrophage response in vivo. However, they also suggest that acute enrichment of only M2-like macrophages after diffuse TBI cannot orchestrate neurogenesis, axonal regeneration, or improve WMI. Here, we also discuss our modified TBI model and methods to assess severity, behavioral studies, and propose that IL-4 expressing MSCs may also have relevance in other cavitary diseases or in improving biomaterial integration into tissues.
- Subjects :
- Male
Stromal cell
Traumatic brain injury
Macrophage
mRNA
Immunology
Inflammation
M2
lcsh:RC346-429
MSC
03 medical and health sciences
Cellular and Molecular Neuroscience
Mice
0302 clinical medicine
TBI
Brain Injuries, Traumatic
medicine
Animals
lcsh:Neurology. Diseases of the nervous system
030304 developmental biology
0303 health sciences
Stem cell
Microglia
business.industry
General Neuroscience
Regeneration (biology)
Research
Macrophages
Mesenchymal stem cell
Neurogenesis
IL-4
Mesenchymal Stem Cells
medicine.disease
Disease Models, Animal
medicine.anatomical_structure
Neurology
Cancer research
Interleukin-4
medicine.symptom
RNA-seq
business
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 17422094
- Volume :
- 17
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Neuroinflammation
- Accession number :
- edsair.doi.dedup.....acf1fc775f9cfccd8ae201215dfb6741