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

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Neurotherapeutics

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.

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Acknowledgments

This work was supported by Progetto ricerca finalizzata FR-CCM-2008-1248388 and FISM2012/R/17 to C.V. We thank Professor Maria Pia Abbracchio and Dr. Davide Lecca, 20133 University of Milan, for useful discussions; and Ilaria Prada (IN CNR, Milan) for assistance with some of the experiments. We also thank the association “Esserci con Cate per i Bimbi”, which supported this work.

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Authors and Affiliations

  1. Department of Neuroscience, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, 20156, Milan, Italy

    Elisa R. Zanier, Francesca Pischiutta, Federica Marchesi, Stefano Fumagalli, Carlo Perego, Emanuela Parotto, Pietro Veglianese & Maria-Grazia De Simoni

  2. CNR Institute of Neuroscience, 20129, Milan, Italy

    Loredana Riganti, Elena Turola & Claudia Verderio

  3. Department of Biotechnology and Translational Medicine, University of Milan, 20129, Milan, Italy

    Loredana Riganti & Elena Turola

  4. Department of Pathophysiology and Transplantation, IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, 20122, Milan, Italy

    Stefano Fumagalli

  5. Institute of Anesthesia and Intensive Care, University of Padova, 35128, Padova, Italy

    Emanuela Parotto

  6. Centro Ricerca Tettamanti, Clinica Pediatrica Università Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, 20900, Monza, Italy

    Paola Vinci & Giovanna D’Amico

  7. Humanitas Clinical and Research Center, 20089, Rozzano, Milan, Italy

    Claudia Verderio

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  1. Elisa R. Zanier
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  2. Francesca Pischiutta
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  6. Stefano Fumagalli
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  9. Paola Vinci
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Correspondence to Claudia Verderio or Maria-Grazia De Simoni.

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Zanier, E.R., Pischiutta, F., Riganti, L. et al. Bone Marrow Mesenchymal Stromal Cells Drive Protective M2 Microglia Polarization After Brain Trauma. Neurotherapeutics 11, 679–695 (2014). https://doi.org/10.1007/s13311-014-0277-y

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