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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.

ABSTRACT: BACKGROUND: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 (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). METHODS:To 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. RESULTS:We 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. CONCLUSION:The 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.

SUBMITTER: Enam SF

PROVIDER: S-EPMC7306141 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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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 Syed Faaiz SF Kader Sajidur Rahman SR Bodkin Nicholas N Lyon Johnathan G JG Calhoun Mark M Azrak Cesar C Tiwari Pooja Munnilal PM Vanover Daryll D Wang Haichen H Santangelo Philip J PJ Bellamkonda Ravi Venkat RV

Journal of neuroinflammation 20200620 1

<h4>Background</h4>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 ...[more]

PMID: 32563258

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Project description:More than 6.5 million patients are burdened by the physical, cognitive, and psychosocial deficits associated with traumatic brain injury (TBI) in the U.S. Despite extensive efforts to develop neuroprotective therapies for this devastating disorder, there have been no successful outcomes in human clinical trials to date. Retrospective studies have shown that ?-adrenergic receptor blockers, specifically propranolol, significantly decrease mortality of TBI through mechanisms not yet fully elucidated but are thought to counterbalance a hyperadrenergic state resulting from a TBI. Conversely, cellular therapies have been shown to improve long-term behavior following TBI, likely by reducing inflammation. Given the nonredundancy in their therapeutic mechanisms, we hypothesized that a combination of acute propranolol followed by mesenchymal stem cells (MSCs) isolated from human bone marrow would have additive effects in treating a rodent model of TBI. We have found that the treatments are well-tolerated individually and in combination with no adverse events. MSCs decrease BBB permeability at 96 hours after injury, inhibit a significant accumulation of activated microglia/macrophage in the thalamic region of the brain both short and long term, and enhance neurogenesis short term. Propranolol decreases edema and reduces the number of fully activated microglia at 7 days and the number of semiactivated microglia at 120 days. Combinatory treatment improved cognitive and memory functions 120 days following TBI. Therefore, the results here suggest a new, efficacious sequential treatment for TBI may be achieved using the ?-blocker propranolol followed by MSC treatment.Despite continuous efforts, traumatic brain injury (TBI) remains the leading cause of death and disability worldwide in patients under the age of 44. In this study, an animal model of moderate-severe TBI was treated with an acute dose of propranolol followed by a delayed dose of human mesenchymal stem cells (MSCs), resulting in improved short- and long-term measurements. These results have direct translational application. They reinforce the inevitable clinical trial of MSCs to treat TBI by demonstrating, among other benefits, a notable decrease in chronic neuroinflammation. More importantly, these results demonstrate that MSCs and propranolol, which is increasingly being used clinically for TBI, are compatible treatments that improve overall outcome.

Project description:Background—Mesenchymal stem cells (MSCs) have shown therapeutic potency for treating cardiovascular diseases, but their therapeutic efficacy shows significant heterogeneity depending on their tissue of origin. We herein sought to identify the optimal source of MSCs for cardiovascular disease therapy. Methods—Heart- and bone marrow (BM)-derived GFP+ cells positive for the MSCs marker, Nestin, were flow cytometrically sorted from 7-day-postnatal Nestin-GFP transgenic mice. To study their biological characteristics in vitro, we characterized their self-renewal capacity, multi-lineage differentiation ability, and surface markers. To investigate their therapeutic potential in vivo, we intramyocardially injected Nestin+ cells (3×105) into the infarct border zone of mice subjected to acute myocardial infarction (MI), and performed echocardiography and Masson’s-Trichrome staining at 1 and 3 weeks post-MI. We characterized gene profiles with RNA-sequencing analysis, and analyzed the putative reparative mechanism, that of Periostin-mediated M2 macrophages polarization, by immunofluorescence staining, qPCR, ELISA, and flow cytometry in vivo and in vitro. Results—In vitro, the heart- and BM-derived Nestin+ cells (Nes+cMSCs and Nes+bmMSCs, respectively) were found to possess self-renewal ability, show similar tri-lineage differentiation potentials, and express some MSCs-related surface markers. Importantly, Nes+cMSCs significantly improved cardiac function, attenuated left ventricular (LV) remodeling, and decreased infarct size in the mouse MI model, compared with Nes+bmMSCs- or saline-treated MI controls. Nes+cMSC treatment notably reduced the total number of CD68+ pan-macrophages while inducing the polarization of macrophages toward an anti-inflammatory M2 phenotype in ischemic myocardium, compared with the saline-treated MI control. Periostin, which was highly expressed in Nes+cMSCs, could promote the polarization of M2-subtype macrophages in vitro and in vivo. Finally, Periostin knockdown remarkably reduced the therapeutic effects of Nes+cMSCs, inhibiting the survival and LV remodeling of MI model mice and significantly decreasing the number of M2 macrophages at lesion sites. Conclusions—Nestin+ cMSCs have greater efficacy than Nestin+ bmMSCs for cardiac repair following acute MI, using a reparative mechanism that acts at least partly through Periostin-mediated M2 macrophage polarization.

Dataset Information

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

Publications

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

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