Takuya Maeda1, Kamil Sarkislali1, Camille Leonetti1, Nisha Kapani2, Zaenab Dhari1, Ibtisam Al Haj1, Robert Ulrey3, Patrick J Hanley4, Richard A Jonas5, Nobuyuki Ishibashi6. 1. Children's National Heart Institute, Children's National Hospital, Washington, DC; Center for Neuroscience Research, Children's National Hospital, Washington, DC. 2. George Washington University School of Medicine and Health Science, Washington, DC. 3. Program for Cell Enhancement and Technologies for Immunotherapy, Division of Blood and Marrow Transplantation and Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC. 4. George Washington University School of Medicine and Health Science, Washington, DC; Program for Cell Enhancement and Technologies for Immunotherapy, Division of Blood and Marrow Transplantation and Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC. 5. Children's National Heart Institute, Children's National Hospital, Washington, DC; Center for Neuroscience Research, Children's National Hospital, Washington, DC; George Washington University School of Medicine and Health Science, Washington, DC. 6. Children's National Heart Institute, Children's National Hospital, Washington, DC; Center for Neuroscience Research, Children's National Hospital, Washington, DC; George Washington University School of Medicine and Health Science, Washington, DC. Electronic address: nishibas@childrensnational.org.
Abstract
BACKGROUND: Neurodevelopmental impairment is an important challenge for survivors after neonatal surgery with cardiopulmonary bypass (CPB). The subventricular zone, where most neural stem/progenitors originate, plays a critical role in cortical maturation of the frontal lobe. Promoting neurogenesis in the subventricular zone is therefore a potential therapeutic target for preserving cortical growth. Mesenchymal stromal cells (MSCs) promote endogenous regeneration in the rodent brain. We investigated the impact of MSC delivery through CPB on neural stem/progenitor cells and neuroblasts (ie, young neurons) in the piglet subventricular zone. METHODS: Two-week-old piglets (n = 12) were randomly assigned to one of three groups: (1) control, (2) deep hypothermic circulatory arrest, and (3) circulatory arrest, followed by MSC administration. MSCs (10 × 106 per kg) were delivered through CPB during the rewarming period. Neural stem/progenitors, proliferating cells, and neuroblasts were identified with immunohistochemistry at 3 hours after CPB. RESULTS: CPB-induced insults caused an increased proliferation of neural stem/progenitors (P < .05). MSC delivery reduced the acute proliferation. MSC treatment increased the number of neuroblasts in the outer region of the subventricular zone (P < .05) where they form migrating chains toward the frontal lobe. Conversely, the thickness of the neuroblast-dense band along the lateral ventricle was reduced after treatment (P < .05). These findings suggest that MSC treatment changes neuroblast distribution within the subventricular zone. CONCLUSIONS: MSC delivery through CPB has the potential to mitigate effects of CPB on neural stem/progenitor cells and to promote migration of neuroblasts. Further investigation is necessary to determine the long-term effect of MSC treatment during CPB on postnatal neurogenesis.
BACKGROUND: Neurodevelopmental impairment is an important challenge for survivors after neonatal surgery with cardiopulmonary bypass (CPB). The subventricular zone, where most neural stem/progenitors originate, plays a critical role in cortical maturation of the frontal lobe. Promoting neurogenesis in the subventricular zone is therefore a potential therapeutic target for preserving cortical growth. Mesenchymal stromal cells (MSCs) promote endogenous regeneration in the rodent brain. We investigated the impact of MSC delivery through CPB on neural stem/progenitor cells and neuroblasts (ie, young neurons) in the piglet subventricular zone. METHODS: Two-week-old piglets (n = 12) were randomly assigned to one of three groups: (1) control, (2) deep hypothermic circulatory arrest, and (3) circulatory arrest, followed by MSC administration. MSCs (10 × 106 per kg) were delivered through CPB during the rewarming period. Neural stem/progenitors, proliferating cells, and neuroblasts were identified with immunohistochemistry at 3 hours after CPB. RESULTS: CPB-induced insults caused an increased proliferation of neural stem/progenitors (P < .05). MSC delivery reduced the acute proliferation. MSC treatment increased the number of neuroblasts in the outer region of the subventricular zone (P < .05) where they form migrating chains toward the frontal lobe. Conversely, the thickness of the neuroblast-dense band along the lateral ventricle was reduced after treatment (P < .05). These findings suggest that MSC treatment changes neuroblast distribution within the subventricular zone. CONCLUSIONS: MSC delivery through CPB has the potential to mitigate effects of CPB on neural stem/progenitor cells and to promote migration of neuroblasts. Further investigation is necessary to determine the long-term effect of MSC treatment during CPB on postnatal neurogenesis.
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