Dose Effect of Mesenchymal Stromal Cell Delivery Through Cardiopulmonary Bypass

Kei Kobayashi, Department of Cardiac Surgery, Children's National Hospital, Washington, DC; Center for Neuroscience Research, Children's National Hospital, Washington, DC; Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, DC.
Takuya Maeda, Department of Cardiac Surgery, Children's National Hospital, Washington, DC; Center for Neuroscience Research, Children's National Hospital, Washington, DC; Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, DC.
Mobolanle Ayodeji, Center for Neuroscience Research, Children's National Hospital, Washington, DC; Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, DC.
Shao Ching Tu, Center for Neuroscience Research, Children's National Hospital, Washington, DC; Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, DC; Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri.
Alice Chen, Center for Neuroscience Research, Children's National Hospital, Washington, DC; Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, DC; George Washington University, School of Medicine and Health Sciences, George Washington University, Washington, DC.
May Rajtboriraks, Center for Neuroscience Research, Children's National Hospital, Washington, DC; Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, DC; Department of Biomedical Engineering, The Catholic University of America, Washington, DC.
Chao-Hsiung Hsu, Molecular Imaging Laboratory, Department of Radiology, Howard University, Washington, DC.
Tsang-Wei Tu, Molecular Imaging Laboratory, Department of Radiology, Howard University, Washington, DC; Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Paul C. Wang, Molecular Imaging Laboratory, Department of Radiology, Howard University, Washington, DC; Department of Electrical Engineering, Fu Jen Catholic University, Taipei, Taiwan.
Patrick J. Hanley, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC; Program for Cell Enhancement and Technologies for Immunotherapy, Division of Blood and Marrow Transplantation, Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC.
Richard A. Jonas, Department of Cardiac Surgery, Children's National Hospital, Washington, DC; Center for Neuroscience Research, Children's National Hospital, Washington, DC; Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, DC; Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Nobuyuki Ishibashi, Department of Cardiac Surgery, Children's National Hospital, Washington, DC; Center for Neuroscience Research, Children's National Hospital, Washington, DC; Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, DC; Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC; Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC. Electronic address: nishibas@childrensnational.org.

Document Type

Journal Article

Publication Date

8-8-2022

Journal

The Annals of thoracic surgery

DOI

10.1016/j.athoracsur.2022.07.035

Abstract

BACKGROUND: Neurologic impairments are a significant concern for survivors after pediatric cardiac surgery with cardiopulmonary bypass (CPB). We have previously shown that mesenchymal stromal cell (MSC) delivery through CPB has the potential to mitigate the effects of CPB on neural stem/progenitor cells. This study assessed the dose effects of MSCs. METHODS: Piglets (n = 20) were randomly assigned to 1 of 4 groups: control, CPB, or CPB followed by MSC administration with low and high doses (10 × 10 and 100 × 10 cells per kilogram). We assessed acute dose effect on cell distribution, multiorgan functions, systemic inflammation, microglia activation, and neural stem/progenitor cell activities. RESULTS: By magnetic resonance imaging, approximately 10 times more MSCs were detected within the entire brain after high-dose delivery than after low-dose delivery. No adverse events affecting hemodynamics, various biomarkers, and neuroimaging were detected after high-dose MSC delivery. High-dose MSCs significantly increased circulating levels of interleukin 4 after CPB. Both MSC groups normalized microglia activation after CPB, demonstrating MSC-induced reduction in cerebral inflammation. There was a significant increase in neuroblasts in the subventricular zone in both treatment groups. The thickness of the most active neurogenic area within the subventricular zone was significantly increased after high-dose treatment compared with CPB and low-dose MSCs, suggesting dose-dependent effects on the neurogenic niche. CONCLUSIONS: MSC delivery through CPB is feasible up to 100 × 10 cells per kilogram. MSC treatment during cardiac surgery has the potential to reduce systemic and cerebral inflammation and to modulate responses of an active neurogenic niche to CPB. Further investigation is necessary to assess the long-term effects and to develop a more complete dose-response curve.

Department

Pediatrics

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