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Extracellular vesicles from mesenchymal stem cells reduce microglial-mediated neuroinflammation after cortical injury in aged Rhesus monkeys

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Abstract

Cortical injury, such as injuries after stroke or age-related ischemic events, triggers a cascade of degeneration accompanied by inflammatory responses that mediate neurological deficits. Therapeutics that modulate such neuroinflammatory responses in the aging brain have the potential to reduce neurological dysfunction and promote recovery. Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) are lipid-bound, nanoscale vesicles that can modulate inflammation and enhance recovery in rodent stroke models. We recently assessed the efficacy of intravenous infusions of MSC-EVs (24-h and 14-days post-injury) as a treatment in aged rhesus monkeys (Macaca mulatta) with cortical injury that induced impairment of fine motor function of the hand. Aged monkeys treated with EVs after injury recovered motor function more rapidly and more fully than aged monkeys given a vehicle control. Here, we describe EV-mediated inflammatory changes using histological assays to quantify differences in markers of neuroinflammation in brain tissue between EV and vehicle-treated aged monkeys. The activation status of microglia, the innate macrophages of the brain, is critical to cell fate after injury. Our findings demonstrate that EV treatment after injury is associated with greater densities of ramified, homeostatic microglia, along with reduced pro-inflammatory microglial markers. These findings are consistent with a phenotypic switch of inflammatory hypertrophic microglia towards anti-inflammatory, homeostatic functions, which was correlated with enhanced functional recovery. Overall, our data suggest that EVs reduce neuroinflammation and shift microglia towards restorative functions. These findings demonstrate the therapeutic potential of MSC-derived EVs for reducing neuroinflammation after cortical injury in the aged brain.

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Data availability

The data that support the findings in this study are available from the corresponding author upon request.

Abbreviations

EVs:

Extracellular vesicles

MSCs:

Mesenchymal stem cells

PG:

Perilesional gray matter

SW:

Sublesional white matter

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Acknowledgments

We would like to acknowledge our staff, Penny Schultz and Karen Slater, and graduate students, Karen Bottenfield, Katelyn Trecartin, Samantha Calderazzo, and Ajay Uprety, for their invaluable assistance with this study.

Funding

This work was supported by the NIH grants R21-NS102991, R21NS111174, and U01-NS076474 and the National Center for Advancing Translational Sciences, National Institutes of Health, through BU-CTSI Grant Number 1UL1TR001430.

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Authors and Affiliations

  1. Deparment of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, 700 Albany Street, W701, Boston, MA, 02118, USA

    Veronica Go & Douglas L. Rosene

  2. Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, 02118, USA

    Bethany G. E. Bowley, Monica A. Pessina, Maria Medalla & Tara L. Moore

  3. Department of Neurology, Henry Ford Health Systems, Detroit, 48202, USA

    Zheng Gang Zhang, Michael Chopp & Benjamin Buller

  4. Department of Physics, Oakland University, Rochester, 48309, USA

    Michael Chopp

  5. Yerkes Primate Center, Emory University, Atlanta, 30322, USA

    Douglas L. Rosene

  6. Stemetix, Inc., Needham, 02492, USA

    Seth P. Finklestein

  7. Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, USA

    Seth P. Finklestein

Authors
  1. Veronica Go
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  2. Bethany G. E. Bowley
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  3. Monica A. Pessina
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  4. Zheng Gang Zhang
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  5. Michael Chopp
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  6. Seth P. Finklestein
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  7. Douglas L. Rosene
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  8. Maria Medalla
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  9. Benjamin Buller
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  10. Tara L. Moore
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Correspondence to Veronica Go.

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Go, V., Bowley, B.G.E., Pessina, M.A. et al. Extracellular vesicles from mesenchymal stem cells reduce microglial-mediated neuroinflammation after cortical injury in aged Rhesus monkeys. GeroScience 42, 1–17 (2020). https://doi.org/10.1007/s11357-019-00115-w

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  • DOI: https://doi.org/10.1007/s11357-019-00115-w

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