Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats
Open accessAbstract
Background and Purpose—: Cell therapy with bone marrow stromal cells (BMSCs) improves functional recovery after stroke in nondiabetic rats. However, its effect on diabetics with stroke is unknown. This study investigated the effect of BMSCs on stroke outcome in Type 1 diabetic (T1DM) rats. Methods—: T1DM was induced in adult male Wistar rats by injecting streptozotocin. Nondiabetic and T1DM rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO), treated with or without BMSCs (3×10 6 ) at 24 hours after MCAO, and monitored for 14 days. Results—: Functional benefit was not detected in T1DM-MCAO treated with BMSC rats compared with corresponding T1DM-MCAO controls. BMSC treatment in T1DM-MCAO rats had increased mortality, blood–brain barrier leakage, brain hemorrhage, and angiogenesis. Internal carotid artery neointimal formation and cerebral arteriole narrowing/occlusion were also observed in T1DM-MCAO+BMSCs rats compared with T1DM-MCAO controls ( P <0.05), but not in nondiabetic stroke rats. We further studied the underlying mechanisms responsible for BMSC-induced blood–brain barrier leakage and accelerated vascular damage in T1DM-MCAO rats. We found that the expression of angiogenin (an angiogenic factor) and ED1 (a marker for macrophages) was significantly increased in the T1DM-MCAO+BMSC rats in the ischemic brain and internal carotid artery compared with nontreated T1DM-MCAO rats, but not in nondiabetic stroke rats. Conclusions—: BMSC therapy in T1DM-MCAO rats does not improve functional outcome. On the contrary, it increases blood–brain barrier leakage and cerebral artery neointimal formation, and arteriosclerosis, which possibly is due to increased expression of angiogenin. Thus, BMSC treatment starting 24 hours after MCAO may not be beneficial for diabetic subjects with stroke.
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These abnormalities were attributed to increased angiogenin expression in brain and brain-supplying arteries of rats with diabetes.
“These abnormalities were attributed to increased angiogenin expression in the brain and brain-supplying arteries of rats with diabetes.80”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [80]
In histochemical studies, bone-marrow-derived stromal cells exacerbated neointima formation and arteriole narrowing and increased macrophage accumulation in blood vessels of rats with diabetes.
“In histo chemical studies, neointima formation and arteriole narrowing were exacerbated by bone-marrow-derived stromal cells in rats with diabetes, as was macrophage accumulation in blood vessels.80”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [80]
The relevance of associated diseases for efficacy of plasticity-promoting therapies was recently shown in rats with streptozotocin-induced diabetes.
“The relevance of associated diseases for the efficacy of plasticity-promoting therapies was recently shown in rats with streptozotocin-induced diabetes.80”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [80]
In rats with diabetes, bone-marrow-derived stromal cell treatment did not improve neurological recovery and increased mortality, blood-brain barrier leakage, and brain haemorrhage.
“Para doxically, treatment with bone-marrow-derived stromal cells did not improve neurological recovery in rats with diabetes, but increased mortality, blood–brain barrier leakage, and brain haemorrhage.80”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [80]
Such findings have been reported for severe associated systemic diseases (diabetic vasculopathy), after systemic thrombolysis, and when restorative treatments were initiated at inappropriate timepoints (before stroke).
“Such findings have been reported for severe associated systemic diseases (ie, diabetic vasculopathy),80 subsequent to systemic thrombolysis,91,92 and when restorative treat ments were initiated at inappropriate timepoints (ie, before stroke;93 table).”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [80]
Animal studies have identified medical conditions that specifically undermine neurorestorative therapies by making the brain prone to detrimental responses.
“Animal studies have identified medical conditions that specifically undermine neurorestorative therapies by making the brain prone to detrimental responses.”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [80]
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References 25 · Cited by 120
- Authors
- Chen, J., Ye, X., Yan, T., Zhang, C., Yang, X.-P., Cui, X., Cui, Y., Zacharek, A., Roberts, C., Liu, X., Dai, X., Lu, M., & Chopp, M.
- Affiliations
- Tianjin University (CN)
- From Neurology (J.C., T.Y., C.Z., Xu Cui, Yishen Cui, A.Z., C.R., M.C.), Internal Medicine (X.-P.Y., X.D.), Hypertension & Vascular Research Division, and Biostatistics and Research Epidemiology (M.L.), Henry Ford Hospital, Detroit, MI; Neurology (X.Y., X.L.), Jinling Hospital, Nanjing University School of Medicine, Nanjing, China; Neurology (T.Y.), Tianjin General Hospital, Tianjin University School of Medicine, Tianjin, China; and Physics (M.C.), Oakland University, Rochester, MI.
- ORCID
- Venue
- Stroke
- Published
- 2011-12
- Volume
- 42
- Issue
- 12
- Pages
- 3551-3558
- ISSN
- 0039-2499 (ISSN-L)
- 1524-4628
- PMC
- PMC3264886
- OpenAlex
- W2069992465
- Cited by
- 120
- References
- 25
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 1 · 2021: 10 · 2020: 4 · 2019: 12 · 2018: 7 · 2017: 18 · 2016: 14 · 2015: 12 · 2014: 10 · 2013: 14 · 2012: 4
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Stroke (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- Ministerul Cercetării, Inovării şi Digitalizării
- National Institute on Aging (R01AG037506, R01AG031811)
- National Institute of Neurological Disorders and Stroke (R41NS064708)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- mesenchymal stem cells, cell therapy, type 1 diabetes, middle cerebral artery occlusion, blood-brain barrier disruption, neointima formation, arteriosclerosis, angiogenin, macrophages, cerebral hemorrhage, angiogenesis, streptozotocin-induced diabetes
- MeSH terms
- Animals, Arteriosclerosis, Blood-Brain Barrier, Diabetes Mellitus, Experimental, Male, Neovascularization, Pathologic, Bone Marrow Transplantation, Stromal Cells, Rats, Wistar, Recovery of Function, Intracranial Hemorrhages, Stroke, Rats
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