An enriched environment prevents diabetes-induced cognitive impairment in rats by enhancing exosomal miR-146a secretion from endogenous bone marrow-derived mesenchymal stem cells

Increasing evidence suggests that an enriched environment (EE) ameliorates cognitive impairment by promoting repair of brain damage. However, the mechanisms by which this occurs have not been determined. To address this issue, we investigated whether an EE enhanced the capability of endogenous bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) to prevent hippocampal damage due to diabetes by focusing on miRNA carried in BM-MSC-derived exosomes. In diabetic streptozotocin (STZ) rats housed in an EE (STZ/EE), cognitive impairment was significantly reduced, and both neuronal and astroglial damage in the hippocampus was alleviated compared with STZ rats housed in conventional cages (STZ/CC). BM-MSCs isolated from STZ/CC rats had functional and morphological abnormalities that were not detected in STZ/EE BM-MSCs. The miR-146a levels in exosomes in conditioned medium of cultured BM-MSCs and serum from STZ/CC rats were decreased compared with non-diabetic rats, and the level was restored in STZ/EE rats. Thus, the data suggest that increased levels of miR-146a in sera were derived from endogenous BM-MSCs in STZ/EE rats. To examine the possibility that increased miR-146a in serum may exert anti-inflammatory effects on astrocytes in diabetic rats, astrocytes transfected with miR-146a were stimulated with advanced glycation end products (AGEs) to mimic diabetic conditions. The expression of IRAK1, NF-κB, and tumor necrosis factor-α was significantly higher in AGE-stimulated astrocytes, and these factors were decreased in miR-146a-transfected astrocytes. These results suggested that EEs stimulate up-regulation of exosomal miR-146a secretion by endogenous BM-MSCs, which exerts anti-inflammatory effects on damaged astrocytes and prevents diabetes-induced cognitive impairment.

[1]  Xiaobing Fu,et al.  Mesenchymal stem cells-derived exosomal microRNAs contribute to wound inflammation , 2016, Science China Life Sciences.

[2]  B. Bussolati,et al.  Extracellular vesicles in renal tissue damage and regeneration. , 2016, European journal of pharmacology.

[3]  M. Fujimiya,et al.  Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes , 2016, Scientific Reports.

[4]  L. Lanting,et al.  Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy. , 2016, Journal of the American Society of Nephrology : JASN.

[5]  C. Giachino,et al.  Senescence in Human Mesenchymal Stem Cells: Functional Changes and Implications in Stem Cell-Based Therapy , 2016, International journal of molecular sciences.

[6]  M. Fujimiya,et al.  Bone marrow-derived mesenchymal stem cells improve diabetes-induced cognitive impairment by exosome transfer into damaged neurons and astrocytes , 2016, Scientific Reports.

[7]  K. Pusic,et al.  Environmental Enrichment Stimulates Immune Cell Secretion of Exosomes that Promote CNS Myelination and May Regulate Inflammation , 2016, Cellular and Molecular Neurobiology.

[8]  M. Alipour,et al.  Alteration in Inflammation-related miR-146a Expression in NF-KB Signaling Pathway in Diabetic Rat Hippocampus , 2016, Advanced pharmaceutical bulletin.

[9]  A. Elbana,et al.  Role of Endogenous Bone Marrow Stem Cells Mobilization in Repair of Damaged Inner Ear in Rats , 2015, International journal of stem cells.

[10]  Lei Jiang,et al.  The Neuroprotective Effect of Liraglutide is Mediated by Glucagon-Like Peptide 1 Receptor-Mediated Activation of cAMP/PKA/CREB Pathway , 2015, Cellular Physiology and Biochemistry.

[11]  Kenneth K. Wu,et al.  High Glucose Induces Bone Marrow-Derived Mesenchymal Stem Cell Senescence by Upregulating Autophagy , 2015, PloS one.

[12]  Ha Won Kim,et al.  Exosomes Secreted from CXCR4 Overexpressing Mesenchymal Stem Cells Promote Cardioprotection via Akt Signaling Pathway following Myocardial Infarction , 2015, Stem cells international.

[13]  Dong Hoon Lee,et al.  Type 1 diabetes alters astrocytic properties related with neurotransmitter supply, causing abnormal neuronal activities , 2015, Brain Research.

[14]  A. Behfar,et al.  Differential Cytotoxicity of Corticosteroids on Human Mesenchymal Stem Cells , 2015, Clinical orthopaedics and related research.

[15]  E. Sijbrands,et al.  Decreased Serum Level of miR-146a as Sign of Chronic Inflammation in Type 2 Diabetic Patients , 2014, PloS one.

[16]  S. Booth,et al.  MicroRNA-146a: A Dominant, Negative Regulator of the Innate Immune Response , 2014, Front. Immunol..

[17]  R. Agrawal,et al.  Deterioration of plasticity and metabolic homeostasis in the brain of the UCD-T2DM rat model of naturally occurring type-2 diabetes. , 2014, Biochimica et biophysica acta.

[18]  G. Olmos,et al.  Tumor Necrosis Factor Alpha: A Link between Neuroinflammation and Excitotoxicity , 2014, Mediators of inflammation.

[19]  I. Patro,et al.  Astrocytic and microglial response in experimentally induced diabetic rat brain , 2014, Metabolic Brain Disease.

[20]  Juan Zhang,et al.  Early enriched environment induces an increased conversion of proBDNF to BDNF in the adult rat's hippocampus , 2014, Behavioural Brain Research.

[21]  M. Fujimiya,et al.  Mesenchymal stem cell therapy ameliorates diabetic hepatocyte damage in mice by inhibiting infiltration of bone marrow–derived cells , 2014, Hepatology.

[22]  M. Chopp,et al.  The role of miR-146a in dorsal root ganglia neurons of experimental diabetic peripheral neuropathy , 2014, Neuroscience.

[23]  Nirmal Singh,et al.  Advanced Glycation End Products and Diabetic Complications , 2014, The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology.

[24]  J. Herms,et al.  Structural dynamics of dendritic spines are influenced by an environmental enrichment: an in vivo imaging study. , 2014, Cerebral cortex.

[25]  Yi Li,et al.  The role of astrocytes in mediating exogenous cell‐based restorative therapy for stroke , 2014, Glia.

[26]  Liping Zhang,et al.  Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model , 2013, Journal of Molecular Medicine.

[27]  Jinlong Shi,et al.  Phosphorylation of Mitogen- and Stress-Activated Protein Kinase-1 in Astrocytic Inflammation: A Possible Role in Inhibiting Production of Inflammatory Cytokines , 2013, PloS one.

[28]  M. Achaval,et al.  Enriched environment induces beneficial effects on memory deficits and microglial activation in the hippocampus of type 1 diabetic rats , 2013, Metabolic Brain Disease.

[29]  M. Chopp,et al.  MiR‐133b Promotes Neural Plasticity and Functional Recovery After Treatment of Stroke with Multipotent Mesenchymal Stromal Cells in Rats Via Transfer of Exosome‐Enriched Extracellular Particles , 2013, Stem cells.

[30]  Yufang Shi,et al.  Immunobiology of mesenchymal stem cells , 2013, Cell Death and Differentiation.

[31]  Emmette R. Hutchison,et al.  Evidence for miR‐181 involvement in neuroinflammatory responses of astrocytes , 2013, Glia.

[32]  Shaomin Li,et al.  Environmental Novelty Activates β2-Adrenergic Signaling to Prevent the Impairment of Hippocampal LTP by Aβ Oligomers , 2013, Neuron.

[33]  Xiaoguang Zhang,et al.  Retrieval of Consolidated Spatial Memory in the Water Maze Is Correlated with Expression of pCREB and Egr1 in the Hippocampus of Aged Mice , 2013, Dementia and Geriatric Cognitive Disorders Extra.

[34]  R. S. Sloviter,et al.  Standardized Environmental Enrichment Supports Enhanced Brain Plasticity in Healthy Rats and Prevents Cognitive Impairment in Epileptic Rats , 2013, PloS one.

[35]  L. Messina,et al.  Type 2 Diabetes Restricts Multipotency of Mesenchymal Stem Cells and Impairs Their Capacity to Augment Postischemic Neovascularization in db/db Mice , 2012, Journal of the American Heart Association.

[36]  A. Storch,et al.  Physical activity and environmental enrichment regulate the generation of neural precursors in the adult mouse substantia nigra in a dopamine-dependent manner , 2012, BMC Neuroscience.

[37]  Michael W. Morris,et al.  The Role of MicroRNA-146a in the Pathogenesis of the Diabetic Wound-Healing Impairment , 2012, Diabetes.

[38]  R. Panizzutti,et al.  Astrocyte-induced Synaptogenesis Is Mediated by Transforming Growth Factor β Signaling through Modulation of d-Serine Levels in Cerebral Cortex Neurons* , 2012, The Journal of Biological Chemistry.

[39]  M. Gutiérrez-Fernández,et al.  Trophic factors and cell therapy to stimulate brain repair after ischaemic stroke , 2012, Journal of cellular and molecular medicine.

[40]  P. V. van Rijen,et al.  MicroRNA-146a: A Key Regulator of Astrocyte-Mediated Inflammatory Response , 2012, PloS one.

[41]  Kevin W Eliceiri,et al.  NIH Image to ImageJ: 25 years of image analysis , 2012, Nature Methods.

[42]  Sun Young Lee,et al.  Role of IRAK1 on TNF-induced Proliferation and NF-ĸB Activation in Human Bone Marrow Mesenchymal Stem Cells , 2012, Cellular Physiology and Biochemistry.

[43]  M. Mogi,et al.  Peroxisome Proliferator-Activated Receptor-&ggr; Activation With Angiotensin II Type 1 Receptor Blockade Is Pivotal for the Prevention of Blood-Brain Barrier Impairment and Cognitive Decline in Type 2 Diabetic Mice , 2012, Hypertension.

[44]  J. Morrison,et al.  The ageing cortical synapse: hallmarks and implications for cognitive decline , 2012, Nature Reviews Neuroscience.

[45]  C. Théry.  Exosomes: secreted vesicles and intercellular communications , 2011, F1000 biology reports.

[46]  R. Gomez,et al.  Enriched environment prevents memory deficits in type 1 diabetic rats , 2011, Behavioural Brain Research.

[47]  P. Roig,et al.  Short-Term Environmental Enrichment Enhances Adult Neurogenesis, Vascular Network and Dendritic Complexity in the Hippocampus of Type 1 Diabetic Mice , 2010, PloS one.

[48]  M. Sofroniew,et al.  Astrocytes: biology and pathology , 2009, Acta Neuropathologica.

[49]  Kaleb M. Pauley,et al.  miR-146a Is Critical for Endotoxin-induced Tolerance , 2009, The Journal of Biological Chemistry.

[50]  H. Danker-Hopfe,et al.  β/A4-Amyloid increases nerve growth factor production in rat primary hippocampal astrocyte cultures , 2007, International Journal of Developmental Neuroscience.

[51]  Li-Huei Tsai,et al.  Recovery of learning and memory is associated with chromatin remodelling , 2007, Nature.

[52]  F. Mora,et al.  Stress, prefrontal cortex and environmental enrichment: Studies on dopamine and acetylcholine release and working memory performance in rats , 2007, Behavioural Brain Research.

[53]  A. Hannan,et al.  Enriched environments, experience-dependent plasticity and disorders of the nervous system , 2006, Nature Reviews Neuroscience.

[54]  Andrew Scutt,et al.  Aging of mesenchymal stem cells , 2006, Ageing Research Reviews.

[55]  P. Scheltens,et al.  Risk of dementia in diabetes mellitus: a systematic review , 2006, The Lancet Neurology.

[56]  Lei Cao,et al.  VEGF, a mediator of the effect of experience on hippocampal neurogenesis. , 2006, Current Alzheimer research.

[57]  A. Lima,et al.  Neuronal and astroglial alterations in the hippocampus of a mouse model for type 1 diabetes , 2005, Brain Research.

[58]  R. Judd,et al.  Effects of diabetes mellitus on astrocyte GFAP and glutamate transporters in the CNS , 2004, Glia.

[59]  M Orrell,et al.  Cognitive rehabilitation and cognitive training for early-stage Alzheimer's disease and vascular dementia. , 2003, The Cochrane database of systematic reviews.

[60]  F. Gage,et al.  Neural consequences of enviromental enrichment , 2000, Nature Reviews Neuroscience.

[61]  Y. Stern,et al.  Diabetes mellitus and the risk of dementia , 1999, Neurology.

[62]  H. Nishikawa,et al.  Chronic cerebral hypoperfusion by permanent internal carotid ligation produces learning impairment without brain damage in rats , 1997, Neuroscience.

[63]  A. Scutt,et al.  Stolzing A Aging of mesenchymal stem cells , 2006 .

[64]  Martin Orrell,et al.  Cognitive rehabilitation interventions targeting memory functioning in early-stage Alzheimer's disease and vascular dementia , 2001 .

[65]  Julie Kreyenbuhl,et al.  Practice guideline for the treatment of patients with schizophrenia , 1997 .

[66]  Practice guideline for the treatment of patients with Alzheimer's disease and other dementias of late life. American Psychiatric Association. , 1997, The American journal of psychiatry.