Intranasal Delivery of Mesenchymal Stromal Cells Protects against Neonatal Hypoxic⁻Ischemic Brain Injury

Courtney A. McDonald, Zlatikha Djuliannisaa, Maria Petraki, Madison C.B. Paton, Tayla R. Penny, Amy E. Sutherland, Margie Castillo-Melendez, Iona Novak, Graham Jenkin, Michael C. Fahey, Suzanne L. Miller

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Cerebral palsy (CP) is a permanent motor disorder that results from brain injury and neuroinflammation during the perinatal period. Mesenchymal stromal cells (MSCs) have been explored as a therapy in multiple adult neuroinflammatory conditions. Our study examined the therapeutic benefits of intranasal delivery of human umbilical cord tissue (UC) derived-MSCs in a rat model of neonatal hypoxic-ischemic (HI) brain injury. To do this, HI was performed on postnatal day 10 Sprague-Dawley rat pups via permanent ligation of the left carotid artery, followed by a hypoxic challenge of 8% oxygen for 90 min. A total of 200,000 UC-MSCs (10 million/kg) were administered intranasally 24 h post-HI. Motor control was assessed after seven days, followed by post-mortem. Analysis included brain immunohistochemistry, gene analysis and serum cytokine measurement. Neonatal HI resulted in brain injury with significant loss of neurons, particularly in the hippocampus. Intranasal administration of UC-MSCs significantly reduced the loss of brain tissue and increased the number of hippocampal neurons. HI significantly upregulated brain inflammation and expression of pro-inflammatory cytokines, while intranasal UC-MSCs significantly reduced markers of neuroinflammation. This study demonstrated that a clinically relevant dose (10 million/kg) of UC-MSCs was neuroprotective following HI by restoring neuronal cell numbers and reducing brain inflammation. Therefore, intranasal delivery of UC-MSCs may be an effective therapy for neonatal brain injury.

Original languageEnglish
Article number2449
Number of pages15
JournalInternational Journal of Molecular Sciences
Volume20
Issue number10
DOIs
Publication statusPublished - 17 May 2019

Keywords

  • cerebral palsy
  • cord tissue cells
  • mesenchymal stem cells
  • neurodevelopment
  • perinatal brain injury

Cite this

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title = "Intranasal Delivery of Mesenchymal Stromal Cells Protects against Neonatal Hypoxic⁻Ischemic Brain Injury",
abstract = "Cerebral palsy (CP) is a permanent motor disorder that results from brain injury and neuroinflammation during the perinatal period. Mesenchymal stromal cells (MSCs) have been explored as a therapy in multiple adult neuroinflammatory conditions. Our study examined the therapeutic benefits of intranasal delivery of human umbilical cord tissue (UC) derived-MSCs in a rat model of neonatal hypoxic-ischemic (HI) brain injury. To do this, HI was performed on postnatal day 10 Sprague-Dawley rat pups via permanent ligation of the left carotid artery, followed by a hypoxic challenge of 8{\%} oxygen for 90 min. A total of 200,000 UC-MSCs (10 million/kg) were administered intranasally 24 h post-HI. Motor control was assessed after seven days, followed by post-mortem. Analysis included brain immunohistochemistry, gene analysis and serum cytokine measurement. Neonatal HI resulted in brain injury with significant loss of neurons, particularly in the hippocampus. Intranasal administration of UC-MSCs significantly reduced the loss of brain tissue and increased the number of hippocampal neurons. HI significantly upregulated brain inflammation and expression of pro-inflammatory cytokines, while intranasal UC-MSCs significantly reduced markers of neuroinflammation. This study demonstrated that a clinically relevant dose (10 million/kg) of UC-MSCs was neuroprotective following HI by restoring neuronal cell numbers and reducing brain inflammation. Therefore, intranasal delivery of UC-MSCs may be an effective therapy for neonatal brain injury.",
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Intranasal Delivery of Mesenchymal Stromal Cells Protects against Neonatal Hypoxic⁻Ischemic Brain Injury. / McDonald, Courtney A.; Djuliannisaa, Zlatikha; Petraki, Maria; Paton, Madison C.B.; Penny, Tayla R.; Sutherland, Amy E.; Castillo-Melendez, Margie; Novak, Iona; Jenkin, Graham; Fahey, Michael C.; Miller, Suzanne L.

In: International Journal of Molecular Sciences, Vol. 20, No. 10, 2449, 17.05.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Intranasal Delivery of Mesenchymal Stromal Cells Protects against Neonatal Hypoxic⁻Ischemic Brain Injury

AU - McDonald, Courtney A.

AU - Djuliannisaa, Zlatikha

AU - Petraki, Maria

AU - Paton, Madison C.B.

AU - Penny, Tayla R.

AU - Sutherland, Amy E.

AU - Castillo-Melendez, Margie

AU - Novak, Iona

AU - Jenkin, Graham

AU - Fahey, Michael C.

AU - Miller, Suzanne L.

PY - 2019/5/17

Y1 - 2019/5/17

N2 - Cerebral palsy (CP) is a permanent motor disorder that results from brain injury and neuroinflammation during the perinatal period. Mesenchymal stromal cells (MSCs) have been explored as a therapy in multiple adult neuroinflammatory conditions. Our study examined the therapeutic benefits of intranasal delivery of human umbilical cord tissue (UC) derived-MSCs in a rat model of neonatal hypoxic-ischemic (HI) brain injury. To do this, HI was performed on postnatal day 10 Sprague-Dawley rat pups via permanent ligation of the left carotid artery, followed by a hypoxic challenge of 8% oxygen for 90 min. A total of 200,000 UC-MSCs (10 million/kg) were administered intranasally 24 h post-HI. Motor control was assessed after seven days, followed by post-mortem. Analysis included brain immunohistochemistry, gene analysis and serum cytokine measurement. Neonatal HI resulted in brain injury with significant loss of neurons, particularly in the hippocampus. Intranasal administration of UC-MSCs significantly reduced the loss of brain tissue and increased the number of hippocampal neurons. HI significantly upregulated brain inflammation and expression of pro-inflammatory cytokines, while intranasal UC-MSCs significantly reduced markers of neuroinflammation. This study demonstrated that a clinically relevant dose (10 million/kg) of UC-MSCs was neuroprotective following HI by restoring neuronal cell numbers and reducing brain inflammation. Therefore, intranasal delivery of UC-MSCs may be an effective therapy for neonatal brain injury.

AB - Cerebral palsy (CP) is a permanent motor disorder that results from brain injury and neuroinflammation during the perinatal period. Mesenchymal stromal cells (MSCs) have been explored as a therapy in multiple adult neuroinflammatory conditions. Our study examined the therapeutic benefits of intranasal delivery of human umbilical cord tissue (UC) derived-MSCs in a rat model of neonatal hypoxic-ischemic (HI) brain injury. To do this, HI was performed on postnatal day 10 Sprague-Dawley rat pups via permanent ligation of the left carotid artery, followed by a hypoxic challenge of 8% oxygen for 90 min. A total of 200,000 UC-MSCs (10 million/kg) were administered intranasally 24 h post-HI. Motor control was assessed after seven days, followed by post-mortem. Analysis included brain immunohistochemistry, gene analysis and serum cytokine measurement. Neonatal HI resulted in brain injury with significant loss of neurons, particularly in the hippocampus. Intranasal administration of UC-MSCs significantly reduced the loss of brain tissue and increased the number of hippocampal neurons. HI significantly upregulated brain inflammation and expression of pro-inflammatory cytokines, while intranasal UC-MSCs significantly reduced markers of neuroinflammation. This study demonstrated that a clinically relevant dose (10 million/kg) of UC-MSCs was neuroprotective following HI by restoring neuronal cell numbers and reducing brain inflammation. Therefore, intranasal delivery of UC-MSCs may be an effective therapy for neonatal brain injury.

KW - cerebral palsy

KW - cord tissue cells

KW - mesenchymal stem cells

KW - neurodevelopment

KW - perinatal brain injury

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U2 - 10.3390/ijms20102449

DO - 10.3390/ijms20102449

M3 - Article

VL - 20

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

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ER -