Astrocytic endogenous glial cell derived neurotrophic factor production is enhanced by bone marrow stromal cell transplantation in the ischemic boundary zone after stroke in adult rats
Open accessAbstract
Bone marrow stromal cells (BMSCs) facilitate functional recovery in rats after focal ischemic attack. Growing evidence suggests that the secretion of various bioactive factors underlies BMSCs' beneficial effects. This study investigates the expression of glial cell derived neurotrophic factor (GDNF) in the ischemic hemisphere with or without BMSC administration. Adult male Wistar rats were subjected to 2 h of middle cerebral artery occlusion followed by an injection of 3 × 10 6 BMSCs (n = 11) or phosphate‐buffered saline (n = 10) into the tail vein 24 h later. Animals were sacrificed seven days later. Single and double immunohistochemical staining was performed to measure GDNF, Ki67, doublecortin, and glial fibrillary acidic protein expression as well as the number of apoptotic cells along the ischemic boundary zone (IBZ) and/or in the subventricular zone (SVZ). BMSC treatment significantly increased GDNF expression and decreased the number of apoptotic cells in the IBZ (P < 0.05). GDNF expression was colocalized with GFAP. Meanwhile, BMSCs increased the number of Ki‐67 positive cells and the density of DCX positive migrating neuroblasts (P < 0.05). GDNF expression was significantly increased in single astrocytes collected from animals treated with BMSCs, and in astrocytes cocultured with BMSCs after OGD (P < 0.05). Our data suggest that BMSCs increase GDNF levels in the ischemic hemisphere; the major source of GDNF protein is reactive astrocytes. We propose that the increase of GDNF in response to BMSC administration creates a hospitable environment for local cellular repair as well as for migrating neuroblasts from the SVZ, and thus contributes to the functional improvement. © 2010 Wiley‐Liss, Inc.
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Delivery of bone-marrow-derived stromal cells or mesenchymal stromal cells further increases levels of GDNF and tPA and reduces levels of tPA inhibitor PAI-1.
“Delivery of bone-marrow-derived stromal cells or mesenchymal stromal cells was shown to further increase levels of GDNF66 and tPA68,69 and reduce levels of the tPA inhibitor plasminogen activator inhibitor 1.70”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [66]
After focal cerebral ischaemia, astrocytes de novo express neurotrophic factors such as GDNF and VEGF, and serine proteases such as tPA, in parallel with downregulation of growth-repulsive proteoglycans.
“Subsequent to focal cerebral ischaemia, and in parallel to the downregulation of growth-repulsive proteoglycans, astrocytes de novo express neurotrophic factors, such as glial-cell-line-derived neurotrophic factor (GDNF)66 and VEGF,67 and serine proteases, namely tissue plasminogen activator (tPA).68”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [66]
Despite robust evidence for specific time windows in which neuronal plasticity and angiogenesis are most active, neurorestorative treatments were still successful in animals once brain remodelling was induced months after stroke.
“Despite the robust evidence for specific time windows in which neuronal plasticity and angiogenesis are most active,64,66,67 neurorestorative treatments were still successful in animals once brain remodelling was induced months after the stroke.18,20”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [66]
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- Authors
- Shen, L. H., Li, Y., & Chopp, M.
- Affiliations
- Henry Ford Hospital (US)
- Oakland University (US)
- Corresponding author
- Chopp, M.
- ORCID
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2010-03-29
- Volume
- 58
- Issue
- 9
- Pages
- 1074-1081
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC3096459
- OpenAlex
- W2033898517
- Cited by
- 101
- References
- 51
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 1 · 2020: 5 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 12 · 2015: 8 · 2014: 4 · 2013: 15 · 2012: 14
- FWCI
- 5.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS045041, R01NS066041, P01NS042345)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- glial cell line-derived neurotrophic factor, mesenchymal stem cells, cell transplantation, stroke, reactive astrocytes, neurogenesis, subventricular zone, neuroblast migration, apoptosis, middle cerebral artery occlusion, oxygen-glucose deprivation
- MeSH terms
- Doublecortin Protein, Aging, Animals, Astrocytes, Brain, Brain Ischemia, Male, Neurons, Random Allocation, Bone Marrow Transplantation, Stromal Cells, Rats, Wistar, Apoptosis, Infarction, Middle Cerebral Artery, Stroke, Glial Cell Line-Derived Neurotrophic Factor, Rats, Stem Cell Niche
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