Delayed Double Treatment with Adult-Sourced Adipose-Derived Mesenchymal Stem Cells Increases Striatal Medium-Spiny Neuronal Number, Decreases Striatal Microglial Number, and Has No Subventricular Proliferative Effect, after Acute Neonatal Hypoxia-Ischemia in Male Rats

Perinatal hypoxia-ischemia (HI) is a major cause of striatal injury. Delayed post-treatment with adult-sourced bone marrow-derived mesenchymal stem cells (BMSCs) increased the absolute number of striatal medium-spiny neurons (MSNs) following perinatal HI-induced brain injury. Yet extraction of BMSCs...

Full description

Bibliographic Details
Main Authors: Haylee K. Basham, Benjamin E. Aghoghovwia, Panagiotis Papaioannou, Steve Seo, Dorothy E. Oorschot
Format: Article
Language:English
Published: MDPI AG 2021-07-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/22/15/7862
_version_ 1797525590124789760
author Haylee K. Basham
Benjamin E. Aghoghovwia
Panagiotis Papaioannou
Steve Seo
Dorothy E. Oorschot
author_facet Haylee K. Basham
Benjamin E. Aghoghovwia
Panagiotis Papaioannou
Steve Seo
Dorothy E. Oorschot
author_sort Haylee K. Basham
collection DOAJ
description Perinatal hypoxia-ischemia (HI) is a major cause of striatal injury. Delayed post-treatment with adult-sourced bone marrow-derived mesenchymal stem cells (BMSCs) increased the absolute number of striatal medium-spiny neurons (MSNs) following perinatal HI-induced brain injury. Yet extraction of BMSCs is more invasive and difficult compared to extraction of adipose-derived mesenchymal stem cells (AD-MSCs), which are easily sourced from subcutaneous tissue. Adult-sourced AD-MSCs are also superior to BMSCs in the treatment of adult ischemic stroke. Therefore, we investigated whether delayed post-treatment with adult-sourced AD-MSCs increased the absolute number of striatal MSNs following perinatal HI-induced brain injury. This included investigation of the location of injected AD-MSCs within the brain, which were widespread in the dorsolateral subventricular zone (dlSVZ) at 1 day after their injection. Cells extracted from adult rat tissue were verified to be stem cells by their adherence to tissue culture plastic and their expression of specific ‘cluster of differentiation’ (CD) markers. They were verified to be AD-MSCs by their ability to differentiate into adipocytes and osteocytes in vitro. Postnatal day (PN) 7/8, male Sprague-Dawley rats were exposed to either HI right-sided brain injury or no HI injury. The HI rats were either untreated (HI + Diluent), single stem cell-treated (HI + MSCs×1), or double stem cell-treated (HI + MSCs×2). Control rats that were matched-for-weight and litter had no HI injury and were treated with diluent (Uninjured + Diluent). Treatment with AD-MSCs or diluent occurred either 7 days, or 7 and 9 days, after HI. There was a significant increase in the absolute number of striatal dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32)-positive MSNs in the double stem cell-treated (HI + MSCs×2) group and the normal control group compared to the HI + Diluent group at PN21. We therefore investigated two potential mechanisms for this effect of double-treatment with AD-MSCs. Specifically, did AD-MSCs: (i) increase the proliferation of cells within the dlSVZ, and (ii) decrease the microglial response in the dlSVZ and striatum? It was found that a primary repair mechanism triggered by double treatment with AD-MSCs involved significantly decreased striatal inflammation. The results may lead to the development of clinically effective and less invasive stem cell therapies for neonatal HI brain injury.
first_indexed 2024-03-10T09:15:04Z
format Article
id doaj.art-89c7f1f3092c4366bc1e42717b18f58b
institution Directory Open Access Journal
issn 1661-6596
1422-0067
language English
last_indexed 2024-03-10T09:15:04Z
publishDate 2021-07-01
publisher MDPI AG
record_format Article
series International Journal of Molecular Sciences
spelling doaj.art-89c7f1f3092c4366bc1e42717b18f58b2023-11-22T05:39:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-012215786210.3390/ijms22157862Delayed Double Treatment with Adult-Sourced Adipose-Derived Mesenchymal Stem Cells Increases Striatal Medium-Spiny Neuronal Number, Decreases Striatal Microglial Number, and Has No Subventricular Proliferative Effect, after Acute Neonatal Hypoxia-Ischemia in Male RatsHaylee K. Basham0Benjamin E. Aghoghovwia1Panagiotis Papaioannou2Steve Seo3Dorothy E. Oorschot4Department of Anatomy, School of Biomedical Sciences, and the Brain Health Research Centre, University of Otago, P.O. Box 913, Dunedin 9054, New ZealandDepartment of Anatomy, School of Biomedical Sciences, and the Brain Health Research Centre, University of Otago, P.O. Box 913, Dunedin 9054, New ZealandDepartment of Anatomy, School of Biomedical Sciences, and the Brain Health Research Centre, University of Otago, P.O. Box 913, Dunedin 9054, New ZealandDepartment of Anatomy, School of Biomedical Sciences, and the Brain Health Research Centre, University of Otago, P.O. Box 913, Dunedin 9054, New ZealandDepartment of Anatomy, School of Biomedical Sciences, and the Brain Health Research Centre, University of Otago, P.O. Box 913, Dunedin 9054, New ZealandPerinatal hypoxia-ischemia (HI) is a major cause of striatal injury. Delayed post-treatment with adult-sourced bone marrow-derived mesenchymal stem cells (BMSCs) increased the absolute number of striatal medium-spiny neurons (MSNs) following perinatal HI-induced brain injury. Yet extraction of BMSCs is more invasive and difficult compared to extraction of adipose-derived mesenchymal stem cells (AD-MSCs), which are easily sourced from subcutaneous tissue. Adult-sourced AD-MSCs are also superior to BMSCs in the treatment of adult ischemic stroke. Therefore, we investigated whether delayed post-treatment with adult-sourced AD-MSCs increased the absolute number of striatal MSNs following perinatal HI-induced brain injury. This included investigation of the location of injected AD-MSCs within the brain, which were widespread in the dorsolateral subventricular zone (dlSVZ) at 1 day after their injection. Cells extracted from adult rat tissue were verified to be stem cells by their adherence to tissue culture plastic and their expression of specific ‘cluster of differentiation’ (CD) markers. They were verified to be AD-MSCs by their ability to differentiate into adipocytes and osteocytes in vitro. Postnatal day (PN) 7/8, male Sprague-Dawley rats were exposed to either HI right-sided brain injury or no HI injury. The HI rats were either untreated (HI + Diluent), single stem cell-treated (HI + MSCs×1), or double stem cell-treated (HI + MSCs×2). Control rats that were matched-for-weight and litter had no HI injury and were treated with diluent (Uninjured + Diluent). Treatment with AD-MSCs or diluent occurred either 7 days, or 7 and 9 days, after HI. There was a significant increase in the absolute number of striatal dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32)-positive MSNs in the double stem cell-treated (HI + MSCs×2) group and the normal control group compared to the HI + Diluent group at PN21. We therefore investigated two potential mechanisms for this effect of double-treatment with AD-MSCs. Specifically, did AD-MSCs: (i) increase the proliferation of cells within the dlSVZ, and (ii) decrease the microglial response in the dlSVZ and striatum? It was found that a primary repair mechanism triggered by double treatment with AD-MSCs involved significantly decreased striatal inflammation. The results may lead to the development of clinically effective and less invasive stem cell therapies for neonatal HI brain injury.https://www.mdpi.com/1422-0067/22/15/7862adipose-derived mesenchymal stem cellsadult mesenchymal stem cellslocation of extrinsic stem cells in brainstriatal medium-spiny projection neuronsstriatal microgliasubventricular zone
spellingShingle Haylee K. Basham
Benjamin E. Aghoghovwia
Panagiotis Papaioannou
Steve Seo
Dorothy E. Oorschot
Delayed Double Treatment with Adult-Sourced Adipose-Derived Mesenchymal Stem Cells Increases Striatal Medium-Spiny Neuronal Number, Decreases Striatal Microglial Number, and Has No Subventricular Proliferative Effect, after Acute Neonatal Hypoxia-Ischemia in Male Rats
International Journal of Molecular Sciences
adipose-derived mesenchymal stem cells
adult mesenchymal stem cells
location of extrinsic stem cells in brain
striatal medium-spiny projection neurons
striatal microglia
subventricular zone
title Delayed Double Treatment with Adult-Sourced Adipose-Derived Mesenchymal Stem Cells Increases Striatal Medium-Spiny Neuronal Number, Decreases Striatal Microglial Number, and Has No Subventricular Proliferative Effect, after Acute Neonatal Hypoxia-Ischemia in Male Rats
title_full Delayed Double Treatment with Adult-Sourced Adipose-Derived Mesenchymal Stem Cells Increases Striatal Medium-Spiny Neuronal Number, Decreases Striatal Microglial Number, and Has No Subventricular Proliferative Effect, after Acute Neonatal Hypoxia-Ischemia in Male Rats
title_fullStr Delayed Double Treatment with Adult-Sourced Adipose-Derived Mesenchymal Stem Cells Increases Striatal Medium-Spiny Neuronal Number, Decreases Striatal Microglial Number, and Has No Subventricular Proliferative Effect, after Acute Neonatal Hypoxia-Ischemia in Male Rats
title_full_unstemmed Delayed Double Treatment with Adult-Sourced Adipose-Derived Mesenchymal Stem Cells Increases Striatal Medium-Spiny Neuronal Number, Decreases Striatal Microglial Number, and Has No Subventricular Proliferative Effect, after Acute Neonatal Hypoxia-Ischemia in Male Rats
title_short Delayed Double Treatment with Adult-Sourced Adipose-Derived Mesenchymal Stem Cells Increases Striatal Medium-Spiny Neuronal Number, Decreases Striatal Microglial Number, and Has No Subventricular Proliferative Effect, after Acute Neonatal Hypoxia-Ischemia in Male Rats
title_sort delayed double treatment with adult sourced adipose derived mesenchymal stem cells increases striatal medium spiny neuronal number decreases striatal microglial number and has no subventricular proliferative effect after acute neonatal hypoxia ischemia in male rats
topic adipose-derived mesenchymal stem cells
adult mesenchymal stem cells
location of extrinsic stem cells in brain
striatal medium-spiny projection neurons
striatal microglia
subventricular zone
url https://www.mdpi.com/1422-0067/22/15/7862
work_keys_str_mv AT hayleekbasham delayeddoubletreatmentwithadultsourcedadiposederivedmesenchymalstemcellsincreasesstriatalmediumspinyneuronalnumberdecreasesstriatalmicroglialnumberandhasnosubventricularproliferativeeffectafteracuteneonatalhypoxiaischemiainmalerats
AT benjamineaghoghovwia delayeddoubletreatmentwithadultsourcedadiposederivedmesenchymalstemcellsincreasesstriatalmediumspinyneuronalnumberdecreasesstriatalmicroglialnumberandhasnosubventricularproliferativeeffectafteracuteneonatalhypoxiaischemiainmalerats
AT panagiotispapaioannou delayeddoubletreatmentwithadultsourcedadiposederivedmesenchymalstemcellsincreasesstriatalmediumspinyneuronalnumberdecreasesstriatalmicroglialnumberandhasnosubventricularproliferativeeffectafteracuteneonatalhypoxiaischemiainmalerats
AT steveseo delayeddoubletreatmentwithadultsourcedadiposederivedmesenchymalstemcellsincreasesstriatalmediumspinyneuronalnumberdecreasesstriatalmicroglialnumberandhasnosubventricularproliferativeeffectafteracuteneonatalhypoxiaischemiainmalerats
AT dorothyeoorschot delayeddoubletreatmentwithadultsourcedadiposederivedmesenchymalstemcellsincreasesstriatalmediumspinyneuronalnumberdecreasesstriatalmicroglialnumberandhasnosubventricularproliferativeeffectafteracuteneonatalhypoxiaischemiainmalerats