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Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats.

ABSTRACT: 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.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.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.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.

SUBMITTER: Chen J

PROVIDER: S-EPMC3264886 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats.

Chen Jieli J Ye Xinchun X Yan Tao T Zhang Chunling C Yang Xiao-Ping XP Cui Xu X Cui Yishen Y Zacharek Alex A Roberts Cynthia C Liu Xinfeng X Dai Xiangguo X Lu Mei M Chopp Michael M

Stroke 20110922 12

<h4>Background and purpose</h4>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.<h4>Methods</h4>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 with ...[more]

PMID: 21940967

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Project description:: In rats with type 1 diabetes (T1DM), the therapeutic effects and underlying mechanisms of action of stroke treatment were compared between bone-marrow stromal cells (BMSCs) derived from T1DM rats (DM-BMSCs) and BMSCs derived from normal rats (Nor-BMSCs). The novel role of microRNA-145 (miR-145) in mediating DM-BMSC treatment-induced benefits was also investigated. T1DM rats (n = 8 per group) underwent 2 hours of middle cerebral artery occlusion (MCAo) and were treated 24 hours later with the one of the following (5 × 106 cells administered i.v.): (a) phosphate-buffered saline (PBS); (b) Nor-BMSCs; (c) DM-BMSCs; (d) DM-BMSCs with miR-145 overexpression (miR-145+/+DM-BMSCs); or (e) Nor-BMSCs with miR-145 knockdown. Evaluation of functional outcome, vascular and white-matter remodeling and microRNA expression was made, and in vitro studies were performed. In vitro, DM-BMSCs exhibited decreased miR-145 expression and increased survival compared with Nor-BMSCs. Capillary tube formation and axonal outgrowth in cultured primary cortical neurons were significantly increased by DM-BMSC-conditioned medium compared with Nor-BMSCs, and significantly decreased by miR-145+/+DM-BMSC-conditioned medium compared with DM-BMSCs. In T1DM rats in which stroke had been induced (T1DM stroke rats), DM-BMSC treatment significantly improved functional outcome, increased vascular and white matter remodeling, decreased serum miR-145 expression, and increased expression of the miR-145 target genes adenosine triphosphate-binding cassette transporter 1 (ABCA1) and insulin-like growth factor 1 receptor (IGFR1), compared with Nor-BMSCs or PBS treatment. However, miR-145+/+DM-BMSCs significantly increased serum miR-145 expression and decreased brain ABCA1 and IGFR1 expression, as well as attenuated DM-BMSC-induced neurorestorative effects in T1DM-MCAo rats. DM-BMSCs exhibited decreased miR-145 expression. In T1DM-MCAo rats, DM-BMSC treatment improved functional outcome and promoted neurorestorative effects. The miR-145/ABCA1/IGFR1 pathway may contribute to the enhanced DM-BMSCs' functional and neurorestorative effects in T1DM stroke rats.SignificanceIn rats with type 1 diabetes (T1DM), the therapeutic effects and underlying mechanisms of action of stroke treatment were compared between bone-marrow stromal cells (BMSCs) derived from T1DM rats (DM-BMSCs) and BMSCs derived from normal rats (Nor-BMSCs). In vitro, DM-BMSCs and derived exosomes decreased miR-145 expression and increased DM-BMSC survival, capillary tube formation, and axonal outgrowth, compared with Nor-BMSCs; these effects were decreased by DM-BMSCs in which miR-145 was overexpressed. In vivo, compared with Nor-BMSC or phosphate-buffered saline treatment, DM-BMSC treatment improved functional outcome and vascular and white matter remodeling, decreased serum miR-145 expression, and increased expression of the miR-145 target genes ABCA1 and IGFR1. microRNA-145 mediated the benefits induced by DM-BMSC treatment.

Project description:Diabetes mellitus is a group of chronic diseases characterized by high blood glucose levels. Diabetic patients have a higher risk of sustaining osteoporotic fractures than non-diabetic people. The fracture healing is usually impaired in diabetics, and our understanding of the detrimental effects of hyperglycemia on fracture healing is still inadequate. Metformin is the first-line medicine for type 2 diabetes (T2D). However, its effects on bone in T2D patients remain to be studied. To assess the impacts of metformin on fracture healing, we compared the healing process of closed-wound fixed fracture, non-fixed radial fracture, and femoral drill-hole injury models in the T2D mice with and without metformin treatment. Our results demonstrated that metformin rescued the delayed bone healing and remolding in the T2D mice in all injury models. In vitro analysis indicated that compromised proliferation, osteogenesis, chondrogenesis of the bone marrow stromal cells (BMSCs) derived from the T2D mice were rescued by metformin treatment when compared to WT controls. Furthermore, metformin could effectively rescue the impaired detrimental lineage commitment of BMSCs isolated from the T2D mice in vivo as assessed by subcutaneous ossicle formation of the BMSC implants in recipient T2D mice. Moreover, the Safranin O staining of cartilage formation in the endochondral ossification under hyperglycemic condition significantly increased at day 14 post-fracture in the T2D mice receiving metformin treatment. The chondrocyte transcript factors SOX9 and PGC1α, important to maintain chondrocyte homeostasis, were both significantly upregulated in callus tissue isolated at the fracture site of metformin-treated MKR mice on day 12 post-fracture. Metformin also rescued the chondrocyte disc formation of BMSCs isolated from the T2D mice. Taken together, our study demonstrated that metformin facilitated bone healing, more specifically bone formation and chondrogenesis in T2D mouse models.

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Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats.

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Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats.

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