Protection against brain injury after ischemic stroke by intravenous human amnion epithelial cells in combination with tissue plasminogen activator
BackgroundThrombolytic agents such as tissue plasminogen activator (tPA) are the only drug class approved to treat ischemic stroke and are usually administered within 4.5 h. However, only ~20% of ischemic stroke patients are eligible to receive the therapy. We previously demonstrated that early intr...
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2023.1157236/full |
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| author | Liz J. Barreto-Arce Hyun Ah Kim Siow Teng Chan Siow Teng Chan Rebecca Lim Rebecca Lim Grant R. Drummond Henry Ma Thanh G. Phan Christopher G. Sobey Shenpeng R. Zhang |
| author_facet | Liz J. Barreto-Arce Hyun Ah Kim Siow Teng Chan Siow Teng Chan Rebecca Lim Rebecca Lim Grant R. Drummond Henry Ma Thanh G. Phan Christopher G. Sobey Shenpeng R. Zhang |
| author_sort | Liz J. Barreto-Arce |
| collection | DOAJ |
| description | BackgroundThrombolytic agents such as tissue plasminogen activator (tPA) are the only drug class approved to treat ischemic stroke and are usually administered within 4.5 h. However, only ~20% of ischemic stroke patients are eligible to receive the therapy. We previously demonstrated that early intravenous administration of human amnion epithelial cells (hAECs) can limit brain inflammation and infarct growth in experimental stroke. Here, we have tested whether hAECs exert cerebroprotective effects in combination with tPA in mice.MethodsMale C57Bl/6 mice were subjected to middle cerebral artery occlusion for 60 min followed by reperfusion. Immediately following reperfusion, vehicle (saline, n = 31) or tPA (10 mg/kg; n = 73) was administered intravenously. After 30 min of reperfusion, tPA-treated mice were injected intravenously with either hAECs (1×106; n = 32) or vehicle (2% human serum albumin; n = 41). A further 15 sham-operated mice were treated with vehicle (n = 7) or tPA + vehicle (n = 8). Mice were designated to be euthanised at 3, 6 or 24 h post-stroke (n = 21, 31, and 52, respectively), and brains were collected to assess infarct volume, blood–brain barrier (BBB) disruption, intracerebral bleeding and inflammatory cell content.ResultsThere was no mortality within 6 h of stroke onset, but a high mortality occurred in tPA + saline-treated mice between 6 h and 24 h post-stroke in comparison to mice treated with tPA + hAECs (61% vs. 27%, p = 0.04). No mortality occurred within 24 h of sham surgery in mice treated with tPA + vehicle. We focused on early infarct expansion within 6 h of stroke and found that infarction was ~50% larger in tPA + saline- than in vehicle-treated mice (23 ± 3 mm3 vs. 15 ± 2 mm3, p = 0.02) but not in mice receiving tPA + hAECs (13 ± 2 mm3, p < 0.01 vs. tPA + saline) in which intracerebral hAECs were detected. Similar to the profiles of infarct expansion, BBB disruption and intracerebral bleeding in tPA + saline-treated mice at 6 h was 50–60% greater than in vehicle-treated controls (2.6 ± 0.5 vs. 1.6 ± 0.2, p = 0.05) but not after tPA + hAECs treatment (1.7 ± 0.2, p = 0.10 vs. tPA + saline). No differences in inflammatory cell content were detected between treatment groups.ConclusionWhen administered following tPA in acute stroke, hAECs improve safety and attenuate infarct growth in association with less BBB disruption and lower 24 h mortality. |
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| spelling | doaj.art-3e2b1adf1f8240659a98ed887f7274db2023-06-16T04:42:08ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2023-06-011710.3389/fnins.2023.11572361157236Protection against brain injury after ischemic stroke by intravenous human amnion epithelial cells in combination with tissue plasminogen activatorLiz J. Barreto-Arce0Hyun Ah Kim1Siow Teng Chan2Siow Teng Chan3Rebecca Lim4Rebecca Lim5Grant R. Drummond6Henry Ma7Thanh G. Phan8Christopher G. Sobey9Shenpeng R. Zhang10Department of Microbiology, Anatomy, Physiology, and Pharmacology and Centre for Cardiovascular Biology and Disease Research, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, AustraliaDepartment of Microbiology, Anatomy, Physiology, and Pharmacology and Centre for Cardiovascular Biology and Disease Research, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, AustraliaThe Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, AustraliaDepartment of Obstetrics and Gynaecology, Monash University, Clayton, VIC, AustraliaThe Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, AustraliaDepartment of Obstetrics and Gynaecology, Monash University, Clayton, VIC, AustraliaDepartment of Microbiology, Anatomy, Physiology, and Pharmacology and Centre for Cardiovascular Biology and Disease Research, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, AustraliaClinical Trials, Imaging and Informatics (CTI) Division, Stroke and Ageing Research (STARC), Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, AustraliaClinical Trials, Imaging and Informatics (CTI) Division, Stroke and Ageing Research (STARC), Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, AustraliaDepartment of Microbiology, Anatomy, Physiology, and Pharmacology and Centre for Cardiovascular Biology and Disease Research, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, AustraliaDepartment of Microbiology, Anatomy, Physiology, and Pharmacology and Centre for Cardiovascular Biology and Disease Research, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, AustraliaBackgroundThrombolytic agents such as tissue plasminogen activator (tPA) are the only drug class approved to treat ischemic stroke and are usually administered within 4.5 h. However, only ~20% of ischemic stroke patients are eligible to receive the therapy. We previously demonstrated that early intravenous administration of human amnion epithelial cells (hAECs) can limit brain inflammation and infarct growth in experimental stroke. Here, we have tested whether hAECs exert cerebroprotective effects in combination with tPA in mice.MethodsMale C57Bl/6 mice were subjected to middle cerebral artery occlusion for 60 min followed by reperfusion. Immediately following reperfusion, vehicle (saline, n = 31) or tPA (10 mg/kg; n = 73) was administered intravenously. After 30 min of reperfusion, tPA-treated mice were injected intravenously with either hAECs (1×106; n = 32) or vehicle (2% human serum albumin; n = 41). A further 15 sham-operated mice were treated with vehicle (n = 7) or tPA + vehicle (n = 8). Mice were designated to be euthanised at 3, 6 or 24 h post-stroke (n = 21, 31, and 52, respectively), and brains were collected to assess infarct volume, blood–brain barrier (BBB) disruption, intracerebral bleeding and inflammatory cell content.ResultsThere was no mortality within 6 h of stroke onset, but a high mortality occurred in tPA + saline-treated mice between 6 h and 24 h post-stroke in comparison to mice treated with tPA + hAECs (61% vs. 27%, p = 0.04). No mortality occurred within 24 h of sham surgery in mice treated with tPA + vehicle. We focused on early infarct expansion within 6 h of stroke and found that infarction was ~50% larger in tPA + saline- than in vehicle-treated mice (23 ± 3 mm3 vs. 15 ± 2 mm3, p = 0.02) but not in mice receiving tPA + hAECs (13 ± 2 mm3, p < 0.01 vs. tPA + saline) in which intracerebral hAECs were detected. Similar to the profiles of infarct expansion, BBB disruption and intracerebral bleeding in tPA + saline-treated mice at 6 h was 50–60% greater than in vehicle-treated controls (2.6 ± 0.5 vs. 1.6 ± 0.2, p = 0.05) but not after tPA + hAECs treatment (1.7 ± 0.2, p = 0.10 vs. tPA + saline). No differences in inflammatory cell content were detected between treatment groups.ConclusionWhen administered following tPA in acute stroke, hAECs improve safety and attenuate infarct growth in association with less BBB disruption and lower 24 h mortality.https://www.frontiersin.org/articles/10.3389/fnins.2023.1157236/fullischemic strokeneuroprotectionthrombolyticstem cellsmouseinflammation |
| spellingShingle | Liz J. Barreto-Arce Hyun Ah Kim Siow Teng Chan Siow Teng Chan Rebecca Lim Rebecca Lim Grant R. Drummond Henry Ma Thanh G. Phan Christopher G. Sobey Shenpeng R. Zhang Protection against brain injury after ischemic stroke by intravenous human amnion epithelial cells in combination with tissue plasminogen activator Frontiers in Neuroscience ischemic stroke neuroprotection thrombolytic stem cells mouse inflammation |
| title | Protection against brain injury after ischemic stroke by intravenous human amnion epithelial cells in combination with tissue plasminogen activator |
| title_full | Protection against brain injury after ischemic stroke by intravenous human amnion epithelial cells in combination with tissue plasminogen activator |
| title_fullStr | Protection against brain injury after ischemic stroke by intravenous human amnion epithelial cells in combination with tissue plasminogen activator |
| title_full_unstemmed | Protection against brain injury after ischemic stroke by intravenous human amnion epithelial cells in combination with tissue plasminogen activator |
| title_short | Protection against brain injury after ischemic stroke by intravenous human amnion epithelial cells in combination with tissue plasminogen activator |
| title_sort | protection against brain injury after ischemic stroke by intravenous human amnion epithelial cells in combination with tissue plasminogen activator |
| topic | ischemic stroke neuroprotection thrombolytic stem cells mouse inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2023.1157236/full |
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