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Dual effects of carbon monoxide on pericytes and neurogenesis in traumatic brain injury

Nature Medicine volume 22, pages 1335–1341 (2016)Cite this article

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Abstract

At low levels, carbon monoxide (CO) has physiological roles as a second messenger and neuromodulator1,2. Here we assess the effects of CO in a mouse model of traumatic brain injury (TBI). Treatment with CO-releasing molecule (CORM)-3 reduced pericyte death and ameliorated the progression of neurological deficits. In contrast, although treatment with the radical scavenger N-tert-butyl-a-phenylnitrone (PBN) also reduced pericyte death, neurological outcomes were not rescued. As compared to vehicle-treated control and PBN-treated mice, CORM-3-treated mice showed higher levels of phosphorylated neural nitric oxide synthase within neural stem cells (NSCs). Inhibition of nitric oxide synthase diminished the CORM-3-mediated increase in the number of cells that stained positive for both the neuronal marker NeuN and 5-bromo-2′-deoxyuridine (BrdU; a marker for proliferating cells) in vivo, consequently interfering with neurological recovery after TBI. Because NSCs seemed to be in close proximity to pericytes, we asked whether cross-talk between pericytes and NSCs was induced by CORM-3, thereby promoting neurogenesis. In pericyte cultures that were undergoing oxygen and glucose deprivation, conditioned cell culture medium collected after CORM-3 treatment enhanced the in vitro differentiation of NSCs into mature neurons. Taken together, these findings suggest that CO treatment may provide a therapeutic approach for TBI by preventing pericyte death, rescuing cross-talk with NSCs and promoting neurogenesis.

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Figure 1: CORM-3 treatment decreases pericyte damage after TBI.
Figure 2: Treatment with CORM-3 or PBN ameliorates vascular dysfunction after TBI.
Figure 3: CORM-3 rescues functional deficits after TBI.
Figure 4: CORM-3 enhances NOS-mediated neurogenesis via cross-talk between pericytes and NSCs.

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Acknowledgements

This work was supported in part by grants from the US National Institutes of Health (K.H., K.A., M.J.W., C.X., X.W. and E.H.L.), the Rappaport Foundation (E.H.L.), the Research Abroad grant from the National Research Foundation of Korea (Y.K.C., S.-H.K., Y.-M.K. and K.-W.K.) and the Global Research Laboratory Program of Korea (K.-W.K.). The vector expressing the HIF-1α double mutant was kindly provided by G.L. Semenza (Johns Hopkins University School of Medicine).

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Authors and Affiliations

  1. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA

    Yoon Kyung Choi, Takakuni Maki, Emiri T Mandeville, Seong-Ho Koh, Kazuhide Hayakawa, Ken Arai, Changhong Xing, Xiaoying Wang & Eng H Lo

  2. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA

    Yoon Kyung Choi, Takakuni Maki, Emiri T Mandeville, Seong-Ho Koh, Kazuhide Hayakawa, Ken Arai, Changhong Xing, Xiaoying Wang & Eng H Lo

  3. Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea

    Seong-Ho Koh

  4. Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, Republic of Korea

    Young-Myeong Kim

  5. Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, USA

    Michael J Whalen

  6. SNU–Harvard NeuroVascular Protection Research Center, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea

    Kyu-Won Kim

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  1. Yoon Kyung Choi
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  12. Eng H Lo
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Contributions

Y.K.C. and E.H.L. designed experiments and wrote the manuscript; Y.K.C., T.M., E.T.M., C.X., S.-H.K., K.H. and X.W. performed experiments; K.A., Y.-M.K., M.J.W., X.W. and K.-W.K. analyzed and critically discussed the data; and E.H.L. supervised the project.

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Correspondence to Yoon Kyung Choi or Eng H Lo.

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Choi, Y., Maki, T., Mandeville, E. et al. Dual effects of carbon monoxide on pericytes and neurogenesis in traumatic brain injury. Nat Med 22, 1335–1341 (2016). https://doi.org/10.1038/nm.4188

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