Bone Marrow Mesenchymal Stromal Cells Drive Protective M2 Microglia Polarization After Brain Trauma

Abstract

Microglia/macrophages (M) are major contributors to postinjury inflammation, but they may also promote brain repair in response to specific environmental signals that drive classic (M1) or alternative (M2) polarization. We investigated the activation and functional changes of M in mice with traumatic brain injuries and receiving intracerebroventricular human bone marrow mesenchymal stromal cells (MSCs) or saline infusion. MSCs upregulated Ym1 and Arginase-1 mRNA (p<0.001), two M2 markers of protective M polarization, at 3 and 7 d postinjury, and increased the number of Ym1 + cells at 7 d postinjury (p<0.05). MSCs reduced the presence of the lysosomal activity marker CD68 on the membrane surface of CD11b-positive M (p<0.05), indicating reduced phagocytosis. MSC-mediated induction of the M2 phenotype in M was associated with early and persistent recovery of neurological functions evaluated up to 35 days postinjury (p<0.01) and reparative changes of the lesioned microenvironment. In vitro, MSCs directly counteracted the proinflammatory response of primary murine microglia stimulated by tumor necrosis factor-α+interleukin 17 or by tumor necrosis factor-α + interferon-γ and induced M2 proregenerative traits, as indicated by the downregulation of inducible nitric oxide synthase and upregulation of Ym1 and CD206 mRNA (p < 0.01). In conclusion, we found evidence that MSCs can drive the M transcriptional environment and induce the acquisition of an early, persistent M2-beneficial phenotype both in vivo and in vitro. Increased Ym1 expression together with reduced in vivo phagocytosis suggests M selection by MSCs towards the M2a subpopulation, which is involved in growth stimulation and tissue repair.

Increased miR‐124‐3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowthviatheir transfer into neurons

“…In addition, other drugs with similar functions, including glyburide (NCT01454154), minocycline (NCT01058395), NNZ-2566-a synthetic analog of neuron pharmaceuticals (NCT00805818, NCT01366820)-atorvastatin (NCT02024373), and rosuvastatin (NCT00990028) are still in early clinical trials or finished trials without published results (15,16). The stem cell therapy, represented by multipotent mesenchymal stromal cell (MSC) transplantation, could suppress neural inflammation (17) and improve functional recovery after TBI (NCT02028104). Problems of ethics and biosafety have long been concerns that limit its development and further clinical application.…”

Fractalkine Receptor Deficiency Is Associated with Early Protection but Late Worsening of Outcome following Brain Trauma in Mice

“…In our hands, the neuroscore has proven to be a sensitive paradigm for measuring post-traumatic neurologic deficits in mice up to 1 month post-injury. [26][27][28] The neuroscore generates a score for each individual mouse from 4 (normal) to 0 (severely impaired) for each of the following indices: 1) forelimb function, 2) hindlimb function; 3) resistance to lateral right and left pulsion, as previously described. [26][27][28] The best score per mouse is 12.…”

“…Positive CD11b, CD45, CD68, Ym1, and iNOS cells were stained by reaction with 3,3-diaminobenzidine-tetrahydrochloride (Vector Laboratories, Burlingame, CA) as previously described. 28 For each reaction, adequate negative controls were performed. For negative control staining, the primary antibodies were omitted, and no staining was observed.…”

Is Immunomodulation a Principal Mechanism Underlying How Cell-Based Therapies Enhance Stroke Recovery?

“…For example, Ohtaki et al [84] found that intracerebral injection of MSCs leads to activation of M2 neuroprotective microglia in a model of global cerebral ischemia. Zanier et al [85] then found in a TBI model that direct injection of MSCs also induces M2 proregenerative traits made evident by downregulation of nitric oxide synthase and upregulation of Ym1, arginase-1, and CD206 mRNA [85]. Another similar study conducted by Hegyi et al [86] found that MSCs caused polarization of microglia towards a phenotype overexpressing arginase-1, CD86, CD206, IL-10, and prostaglandin E2, and underexpressing tumor necrosis factor-α.…”