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Mouse Bone Marrow-Derived Mesenchymal Stem Cells Alleviate Perinatal Brain Injury Via a CD8+ T Cell Mechanism in a Model of Intrauterine Inflammation

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Abstract

The objective of this study was to determine if mouse bone marrow-derived mesenchymal stem cells (BMMSCs) ameliorate preterm birth and perinatal brain injury induced by intrauterine inflammation (IUI). A mouse model of IUI-induced perinatal brain injury at embryonic (E) day 17 was utilized. BMMSCs were derived from GFP-transgenic mice and phenotypically confirmed to be CD44+, Sca-1+, CD45−, CD34−, CD11b−, and CD11c− by flow cytometry and sorted by fluorescence-activated cell sorting (FACS). Dams were assigned to four groups: phosphate-buffered saline (PBS) + PBS, PBS + BMMSCs, lipopolysaccharide (LPS) + PBS, and LPS + BMMSCs. Following maternal IUI, there was a significant increase in CD8+ T cells in the placentas. Maternally administered BMMSCs trafficked to the fetal side of the placenta and resulted in significantly decreased placental CD8+ T cells. Furthermore, fetal trafficking of maternally administered BMMSCs correlated with an improved performance on offspring neurobehavioral testing in LPS + BMMSC group compared with LPS + PBS group. Our data support that maternal administration of BMMSCs can alleviate perinatal inflammation-induced brain injury and improve neurobehavioral outcomes in the offspring via CD8+ T cell immunomodulation at the feto-placental interface.

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Funding

This work was supported by the Integrated Research Center for Fetal Medicine (I.B.) and Sheikh Abdullah Bugshan Fund (I.B.).

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Authors and Affiliations

  1. Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Hongxi Zhao, Li Xie, Julia L. Clemens, Lu Zong, Michael W. McLane, Hattan Arif, Mia C. Feller, Bei Jia, Yan Zhu, Jun Lei & Irina Burd

  2. Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    Andreas Facciabene

  3. Department of Pediatrics, Johns Hopkins University, Baltimore, MD, 21287, USA

    Maide Ozen

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  1. Hongxi Zhao
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  2. Li Xie
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  3. Julia L. Clemens
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  4. Lu Zong
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  5. Michael W. McLane
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  6. Hattan Arif
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  8. Bei Jia
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  9. Yan Zhu
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  10. Andreas Facciabene
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  12. Jun Lei
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  13. Irina Burd
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Correspondence to Irina Burd.

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Animal study protocols were approved by the Institutional Animal Care and Use Committee at the Johns Hopkins University (No. MO14M326).

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Animals were maintained and used in accordance with National Institute of Health guidelines.

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Zhao, H., Xie, L., Clemens, J.L. et al. Mouse Bone Marrow-Derived Mesenchymal Stem Cells Alleviate Perinatal Brain Injury Via a CD8+ T Cell Mechanism in a Model of Intrauterine Inflammation. Reprod. Sci. 27, 1465–1476 (2020). https://doi.org/10.1007/s43032-020-00157-y

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