Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells
Autor: | Cesar Azrak, Haichen Wang, Mark Calhoun, Daryll Vanover, Syed Faaiz Enam, Johnathan G. Lyon, Nicholas Bodkin, Philip J. Santangelo, Pooja M. Tiwari, Ravi V. Bellamkonda, Sajidur Rahman Kader |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
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 |
Zdroj: | Journal of Neuroinflammation, Vol 17, Iss 1, Pp 1-24 (2020) Journal of Neuroinflammation |
ISSN: | 1742-2094 |
Popis: | 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. |
Databáze: | OpenAIRE |
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