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Neurorestorative Responses to Delayed Human Mesenchymal Stromal Cells Treatment of Stroke in Type 2 Diabetic Rats.

ABSTRACT: Comorbidity of diabetes mellitus and stroke results in worse functional outcome, poor long-term recovery, and extensive vascular damage. We investigated the neurorestorative effects and mechanisms of stroke treatment with human bone marrow-derived mesenchymal stromal cells (hMSCs) in type 2 diabetes mellitus (T2DM) rats.Adult male Wistar rats were induced with T2DM, subjected to 2 hours of middle cerebral artery occlusion (MCAo) and treated via tail-vein injection with (1) PBS (n=8) and (2) hMSCs (n=10; 5×106) at 3 days after MCAo.In T2DM rats, hMSCs administered at 3 days after MCAo significantly improves neurological function without affecting blood glucose, infarct volume, and incidence of brain hemorrhage in comparison to T2DM-MCAo PBS-treated rats. Delayed hMSC treatment of T2DM stroke significantly improves blood-brain barrier integrity, increases vascular and arterial density and cerebral vascular perfusion, and promotes neuroblast cell migration and white matter remodeling as indicated by increased doublecortin, axon, myelin, and neurofilament density, respectively. Delayed hMSC treatment significantly increases platelet-derived growth factor expression in the ischemic brain, decreases proinflammatory M1 macrophage and increases anti-inflammatory M2 macrophage compared to PBS-treated T2DM-MCAo rats. In vitro data show that hMSCs increase subventricular zone explant cell migration and primary cortical neuron neurite outgrowth, whereas inhibition of platelet-derived growth factor decreases hMSC-induced subventricular zone cell migration and axonal outgrowth.In T2DM stroke rats, delayed hMSC treatment significantly improves neurological functional outcome and increases neurorestorative effects and M2 macrophage polarization. Increasing brain platelet-derived growth factor expression may contribute to hMSC-induced neurorestoration.

SUBMITTER: Yan T

PROVIDER: S-EPMC5134897 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Neurorestorative Responses to Delayed Human Mesenchymal Stromal Cells Treatment of Stroke in Type 2 Diabetic Rats.

Yan Tao T Venkat Poornima P Chopp Michael M Zacharek Alex A Ning Ruizhuo R Roberts Cynthia C Zhang Yi Y Lu Mei M Chen Jieli J

Stroke 20161011 11

<h4>Background and purpose</h4>Comorbidity of diabetes mellitus and stroke results in worse functional outcome, poor long-term recovery, and extensive vascular damage. We investigated the neurorestorative effects and mechanisms of stroke treatment with human bone marrow-derived mesenchymal stromal cells (hMSCs) in type 2 diabetes mellitus (T2DM) rats.<h4>Methods</h4>Adult male Wistar rats were induced with T2DM, subjected to 2 hours of middle cerebral artery occlusion (MCAo) and treated via tail ...[more]

PMID: 27729575

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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:Background and purposeDiabetes mellitus is a high-risk factor for ischemic stroke. Diabetic stroke patients suffer worse outcomes, poor long-term recovery, risk of recurrent strokes, and extensive vascular damage. We investigated the neurorestorative effects and the underlying mechanisms of stroke treatment with human umbilical cord blood cells (HUCBCs) in type 2 diabetes mellitus (T2DM) rats.MethodsAdult male T2DM rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo). Three days after MCAo, rats were treated via tail-vein injection with (1) PBS and (2) HUCBCs (5×10(6)), n=10 per group.ResultsHUCBC stroke treatment initiated 3 days after MCAo in T2DM rats did not significantly decrease blood-brain barrier leakage (P=0.1) and lesion volume (P=0.078), but significantly improved long-term functional outcome and decreased brain hemorrhage (P<0.05) when compared with the PBS-treated T2DM MCAo control group. HUCBC treatment significantly promoted white matter remodeling as indicated by increased expression of Bielschowsky silver (axons marker), Luxol fast blue (myelin marker), SMI-31 (neurofilament), and Synaptophysin in the ischemic border zone. HUCBC promoted vascular remodeling and significantly increased arterial and vascular density. HUCBC treatment of stroke in T2DM rats significantly increased M2 macrophage polarization (increased M2 macrophage, CD163and CD 206; decreased M1 macrophage, ED1 and inducible nitric oxide synthase expression) in the ischemic brain compared with PBS-treated T2DM MCAo controls (P<0.05). HUCBC also significantly decreased proinflammatory factors, that is, matrix metalloproteinase 9, receptor for advanced glycation end products and toll-like receptor 4 expression in the ischemic brain.ConclusionsHUCBC treatment initiated 3 days after stroke significantly increased white matter and vascular remodeling in the ischemic brain as well as decreased neuroinflammatory factor expression in the ischemic brain in T2DM rats and promoted M2 macrophage polarization. HUCBC reduction of neuroinflammation and increased vascular and white matter axonal remodeling may contribute to the HUCBC-induced beneficial effects in T2DM stroke rats.

Project description:Background and Purpose- Stroke patients with type 2 diabetes mellitus (T2DM) exhibit increased vascular and white matter damage and have worse prognosis compared with nondiabetic stroke patients. We investigated the neurorestorative effects of exosomes derived from mouse brain endothelial cells (EC-Exo) as treatment for stroke in T2DM mice and investigated the role of miR-126 in mediating EC-Exo-derived therapeutic benefits in T2DM-stroke mice. Methods- Adult, male BKS.Cg-m+/+Leprdb/J (T2DM) mice were subjected to photothrombotic stroke model. T2DM mice were intravenously injected at 3 days after stroke with (1) PBS; (2) liposome mimic (vehicle control, 3×1010); (3) EC-Exo (3×1010); (4) knockdown of miR-126 in EC-Exo (miR-126-/- EC-Exo, 3×1010). Behavioral and cognitive tests were performed, and mice were sacrificed at 28 days after stroke. Results- Compared with non-DM stroke mice, T2DM-stroke mice exhibit significantly decreased serum and brain tissue miR-126 expression. Endothelial cells and EC-Exo contain high levels of miR-126 compared with other cell types or exosomes derived from other types of cells, respectively (smooth muscle cells, astrocytes, and marrow stromal cells). Compared with PBS or liposome mimic treatment, EC-Exo treatment of T2DM-stroke mice significantly improves neurological and cognitive function, increases axon density, myelin density, vascular density, arterial diameter, as well as induces M2 macrophage polarization in the ischemic boundary zone. MiR-126-/- EC-Exo treatment significantly decreases miR-126 expression in serum and brain, as well as attentuates EC-Exo treatment-induced functional improvement and does not significantly increase axon and myelin density, vascular density, arterial diameter or induce M2 macrophage polarization in T2DM-stroke mice. In vitro, EC-Exo treatment significantly increases primary cortical neuron axonal outgrowth and increases endothelial capillary tube formation whereas miR-126-/- EC-Exo attentuates EC-Exo induced capillary tube formation and axonal outgrowth. Conclusions- EC-Exo treatment of stroke promotes neurorestorative effects in T2DM mice. MiR-126 may mediate EC-Exo-induced neurorestorative effects in T2DM mice. Visual Overview- An online visual overview is available for this article.

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Neurorestorative Responses to Delayed Human Mesenchymal Stromal Cells Treatment of Stroke in Type 2 Diabetic Rats.

Publications

Neurorestorative Responses to Delayed Human Mesenchymal Stromal Cells Treatment of Stroke in Type 2 Diabetic Rats.

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