HUCBC Treatment Improves Cognitive Outcome in Rats With Vascular Dementia
Background and purpose: Vascular dementia (VaD) is the second common cause of dementia after Alzheimer’s disease in older people. Yet, there are no FDA approved drugs specifically for VaD. In this study, we have investigated the therapeutic effects of human umbilical cord blood cells (HUCBC) treatme...
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doaj-93c8eedb2b094aa5825d0f52bf417dc72020-11-25T03:20:40ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652020-08-011210.3389/fnagi.2020.00258555063HUCBC Treatment Improves Cognitive Outcome in Rats With Vascular DementiaPoornima Venkat0Lauren Culmone1Michael Chopp2Michael Chopp3Julie Landschoot-Ward4Fengjie Wang5Alex Zacharek6Jieli Chen7Department of Neurology, Henry Ford Hospital, Detroit, MI, United StatesDepartment of Neurology, Henry Ford Hospital, Detroit, MI, United StatesDepartment of Neurology, Henry Ford Hospital, Detroit, MI, United StatesDepartment of Physics, Oakland University, Rochester, MI, United StatesDepartment of Neurology, Henry Ford Hospital, Detroit, MI, United StatesDepartment of Neurology, Henry Ford Hospital, Detroit, MI, United StatesDepartment of Neurology, Henry Ford Hospital, Detroit, MI, United StatesDepartment of Neurology, Henry Ford Hospital, Detroit, MI, United StatesBackground and purpose: Vascular dementia (VaD) is the second common cause of dementia after Alzheimer’s disease in older people. Yet, there are no FDA approved drugs specifically for VaD. In this study, we have investigated the therapeutic effects of human umbilical cord blood cells (HUCBC) treatment on the cognitive outcome, white matter (WM) integrity, and glymphatic system function in rats subject to a multiple microinfarction (MMI) model of VaD.Methods: Male, retired breeder rats were subjected to the MMI model (800 ± 100 cholesterol crystals/300 μl injected into the internal carotid artery), and 3 days later were treated with phosphate-buffered saline (PBS) or HUCBC (5 × 106, i.v.). Sham rats were included as naïve control. Following a battery of cognitive tests, rats were sacrificed at 28 days after MMI and brains extracted for immunohistochemical evaluation and Western blot analysis. To evaluate the glymphatic function, fluorescent tracers (Texas Red dextran, MW: 3 kD and FITC-dextran, MW: 500 kD) was injected into the cisterna magna over 30 min at 14 days after MMI. Rats (3–4/group/time point) were sacrificed at 30 min, 3 h, and 6 h, and the tracer movement analyzed using laser scanning confocal microscopy.Results: Compared to control MMI rats, HUCBC treated MMI rats exhibit significantly improved short-term memory and long-term memory exhibited by increased discrimination index in novel object recognition task with retention delay of 4 h and improved novel odor recognition task with retention delay of 24 h, respectively. HUCBC treatment also improves spatial learning and memory as measured using the Morris water maze test compared to control MMI rats. HUCBC treatment significantly increases axon and myelin density increases oligodendrocyte and oligodendrocyte progenitor cell number and increases Synaptophysin expression in the brain compared to control MMI rats. HUCBC treatment of MMI in rats significantly improves glymphatic function by reversing MMI induced delay in the penetration of cerebrospinal fluid (CSF) into the brain parenchyma via glymphatic pathways and reversing delayed clearance from the brain. HUCBC treatment significantly increases miR-126 expression in serum, aquaporin-4 (AQP4) expression around cerebral vessels, and decreases transforming growth factor-β (TGF-β) protein expression in the brain which may contribute to HUCBC induced improved glymphatic function.Conclusions: HUCBC treatment of an MMI rat model of VaD promotes WM remodeling and improves glymphatic function which together may aid in the improvement of cognitive function and memory. Thus, HUCBC treatment warrants further investigation as a potential therapy for VaD.https://www.frontiersin.org/article/10.3389/fnagi.2020.00258/fullcognitionhuman umbilical cord blood cellsmultiple microinfarctsvascular dementiawhite matter remodeling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Poornima Venkat Lauren Culmone Michael Chopp Michael Chopp Julie Landschoot-Ward Fengjie Wang Alex Zacharek Jieli Chen |
spellingShingle |
Poornima Venkat Lauren Culmone Michael Chopp Michael Chopp Julie Landschoot-Ward Fengjie Wang Alex Zacharek Jieli Chen HUCBC Treatment Improves Cognitive Outcome in Rats With Vascular Dementia Frontiers in Aging Neuroscience cognition human umbilical cord blood cells multiple microinfarcts vascular dementia white matter remodeling |
author_facet |
Poornima Venkat Lauren Culmone Michael Chopp Michael Chopp Julie Landschoot-Ward Fengjie Wang Alex Zacharek Jieli Chen |
author_sort |
Poornima Venkat |
title |
HUCBC Treatment Improves Cognitive Outcome in Rats With Vascular Dementia |
title_short |
HUCBC Treatment Improves Cognitive Outcome in Rats With Vascular Dementia |
title_full |
HUCBC Treatment Improves Cognitive Outcome in Rats With Vascular Dementia |
title_fullStr |
HUCBC Treatment Improves Cognitive Outcome in Rats With Vascular Dementia |
title_full_unstemmed |
HUCBC Treatment Improves Cognitive Outcome in Rats With Vascular Dementia |
title_sort |
hucbc treatment improves cognitive outcome in rats with vascular dementia |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Aging Neuroscience |
issn |
1663-4365 |
publishDate |
2020-08-01 |
description |
Background and purpose: Vascular dementia (VaD) is the second common cause of dementia after Alzheimer’s disease in older people. Yet, there are no FDA approved drugs specifically for VaD. In this study, we have investigated the therapeutic effects of human umbilical cord blood cells (HUCBC) treatment on the cognitive outcome, white matter (WM) integrity, and glymphatic system function in rats subject to a multiple microinfarction (MMI) model of VaD.Methods: Male, retired breeder rats were subjected to the MMI model (800 ± 100 cholesterol crystals/300 μl injected into the internal carotid artery), and 3 days later were treated with phosphate-buffered saline (PBS) or HUCBC (5 × 106, i.v.). Sham rats were included as naïve control. Following a battery of cognitive tests, rats were sacrificed at 28 days after MMI and brains extracted for immunohistochemical evaluation and Western blot analysis. To evaluate the glymphatic function, fluorescent tracers (Texas Red dextran, MW: 3 kD and FITC-dextran, MW: 500 kD) was injected into the cisterna magna over 30 min at 14 days after MMI. Rats (3–4/group/time point) were sacrificed at 30 min, 3 h, and 6 h, and the tracer movement analyzed using laser scanning confocal microscopy.Results: Compared to control MMI rats, HUCBC treated MMI rats exhibit significantly improved short-term memory and long-term memory exhibited by increased discrimination index in novel object recognition task with retention delay of 4 h and improved novel odor recognition task with retention delay of 24 h, respectively. HUCBC treatment also improves spatial learning and memory as measured using the Morris water maze test compared to control MMI rats. HUCBC treatment significantly increases axon and myelin density increases oligodendrocyte and oligodendrocyte progenitor cell number and increases Synaptophysin expression in the brain compared to control MMI rats. HUCBC treatment of MMI in rats significantly improves glymphatic function by reversing MMI induced delay in the penetration of cerebrospinal fluid (CSF) into the brain parenchyma via glymphatic pathways and reversing delayed clearance from the brain. HUCBC treatment significantly increases miR-126 expression in serum, aquaporin-4 (AQP4) expression around cerebral vessels, and decreases transforming growth factor-β (TGF-β) protein expression in the brain which may contribute to HUCBC induced improved glymphatic function.Conclusions: HUCBC treatment of an MMI rat model of VaD promotes WM remodeling and improves glymphatic function which together may aid in the improvement of cognitive function and memory. Thus, HUCBC treatment warrants further investigation as a potential therapy for VaD. |
topic |
cognition human umbilical cord blood cells multiple microinfarcts vascular dementia white matter remodeling |
url |
https://www.frontiersin.org/article/10.3389/fnagi.2020.00258/full |
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