Publications by authors named "Emiri Miura-Yura"

8 Publications

  • Page 1 of 1

The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Promotes Inflammation and Non-Ischemic Heart Failure in Mice.

Circ Res 2021 Sep 28;129(6):684-698. Epub 2021 Jul 28.

Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA (Y.Y., E.M.-Y., K.-D.M., N.C., A.H.P., H.O., K.H., H.D., M.A.E., M.S., Y.W., S.S., K.W.).

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.121.319314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409899PMC
September 2021

Murine models of clonal hematopoiesis to assess mechanisms of cardiovascular disease.

Cardiovasc Res 2021 Jun 23. Epub 2021 Jun 23.

Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Clonal hematopoiesis (CH) is a phenomenon whereby somatic mutations confer a fitness advantage to hematopoietic stem and progenitor cells (HSPC) and thus facilitate their aberrant clonal expansion. These mutations are carried into progeny leukocytes leading to a situation whereby a substantial fraction of an individual's blood cells originate from the HSPC mutant clone. Although this condition rarely progresses to a hematological malignancy, circulating blood cells bearing the mutation have the potential to affect other organ systems as they infiltrate into tissues under both homeostatic and disease conditions. Epidemiological and clinical studies have revealed that CH is highly prevalent in the elderly and is associated with an increased risk of cardiovascular disease and mortality. Recent experimental studies in murine models have assessed the most commonly mutated "driver" genes associated with CH, and have provided evidence for mechanistic connections between CH and cardiovascular disease. A deeper understanding of the mechanisms by which specific CH mutations promote disease pathogenesis is of importance, as it could pave the way for individualized therapeutic strategies targeting the pathogenic CH gene mutations in the future. Here, we review the epidemiology of CH and the mechanistic work from studies using murine disease models, with a particular focus on the strengths and limitations of these experimental systems. We intend for this review to help investigators select the most appropriate models to study CH in the setting of cardiovascular disease.
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http://dx.doi.org/10.1093/cvr/cvab215DOI Listing
June 2021

Secreted Factors from Stem Cells of Human Exfoliated Deciduous Teeth Directly Activate Endothelial Cells to Promote All Processes of Angiogenesis.

Cells 2020 10 31;9(11). Epub 2020 Oct 31.

Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan.

Diabetes is a major risk factor for atherosclerosis and ischemic vascular diseases. Recently, regenerative medicine is expected to be a novel therapy for ischemic diseases. Our previous studies have reported that transplantation of stem cells promoted therapeutic angiogenesis for diabetic neuropathy and ischemic vascular disease in a paracrine manner, but the precise mechanism is unclear. Therefore, we examined whether secreted factors from stem cells had direct beneficial effects on endothelial cells to promote angiogenesis. The soluble factors were collected as conditioned medium (CM) 48 h after culturing stem cells from human exfoliated deciduous teeth (SHED) in serum-free DMEM. SHED-CM significantly increased cell viability of human umbilical vein endothelial cells (HUVECs) in MTT assays and accelerated HUVECs migration in wound healing and Boyden chamber assays. In a Matrigel plug assay of mice, the migrated number of primary endothelial cells was markedly increased in the plug containing SHED-CM or SHED suspension. SHED-CM induced complex tubular structures of HUVECs in a tube formation assay. Furthermore, SHED-CM significantly increased neovascularization from the primary rat aorta, indicating that SHED-CM stimulated primary endothelial cells to promote comprehensive angiogenesis processes. The angiogenic effects of SHED-CM were the same or greater than the effective concentration of VEGF. In conclusion, SHED-CM directly stimulates vascular endothelial cells to promote angiogenesis and is promising for future clinical application.
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http://dx.doi.org/10.3390/cells9112385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693657PMC
October 2020

Deficiency of glucagon gene-derived peptides induces peripheral polyneuropathy in mice.

Biochem Biophys Res Commun 2020 10 19;532(1):47-53. Epub 2020 Aug 19.

Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan. Electronic address:

Although diabetic polyneuropathy (DPN) is the commonest diabetic complication, its pathology remains to be clarified. As previous papers have suggested the neuroprotective effects of glucagon-like peptide-1 in DPN, the current study investigated the physiological indispensability of glucagon gene-derived peptides (GCGDPs) including glucagon-like peptide-1 in the peripheral nervous system (PNS). Neurological functions and neuropathological changes of GCGDP deficient (gcg-/-) mice were examined. The gcg-/- mice showed tactile allodynia and thermal hyperalgesia at 12-18 weeks old, followed by tactile and thermal hypoalgesia at 36 weeks old. Nerve conduction studies revealed a decrease in sensory nerve conduction velocity at 36 weeks old. Pathological findings showed a decrease in intraepidermal nerve fiber densities. Electron microscopy revealed a decrease in circularity and an increase in g-ratio of myelinated fibers and a decrease of unmyelinated fibers in the sural nerves of the gcg-/- mice. Effects of glucagon on neurite outgrowth were examined using an ex vivo culture of dorsal root ganglia. A supraphysiological concentration of glucagon promoted neurite outgrowth. In conclusion, the mice with deficiency of GCGDPs developed peripheral neuropathy with age. Furthermore, glucagon might have neuroprotective effects on the PNS of mice. GCGDPs might be involved in the pathology of DPN.
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http://dx.doi.org/10.1016/j.bbrc.2020.08.007DOI Listing
October 2020

Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction.

JCI Insight 2020 03 26;5(6). Epub 2020 Mar 26.

Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We developed a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived CCR2+ myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived CCR2- cardiac-resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2-mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.
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http://dx.doi.org/10.1172/jci.insight.135204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213793PMC
March 2020

Ranirestat Improved Nerve Conduction Velocities, Sensory Perception, and Intraepidermal Nerve Fiber Density in Rats with Overt Diabetic Polyneuropathy.

J Diabetes Res 2019 18;2019:2756020. Epub 2019 Nov 18.

Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.

Distal sensory-motor polyneuropathy is one of the most frequent diabetic complications. However, few therapies address the etiology of neurodegeneration in the peripheral nervous systems of diabetic patients. Several metabolic mechanisms have been proposed as etiologies of this polyneuropathy. In this study, we revisited one of those mechanisms, the polyol pathway, and investigated the curative effects of a novel strong aldose reductase inhibitor, ranirestat, in streptozotocin-induced diabetic rats with preexisting polyneuropathy. Twelve weeks after the onset of diabetes, rats which had an established polyneuropathy were treated once daily with a placebo, ranirestat, or epalrestat, over 6 weeks. Before and after the treatment, nerve conduction velocities and thermal perception threshold of hindlimbs were examined. After the treatment, intraepidermal fiber density was evaluated. As an ex vivo assay, murine dorsal root ganglion cells were dispersed and cultured with or without 1 mol/l ranirestat for 48 hours. After the culture, neurite outgrowth was quantified using immunological staining. Sensory nerve conduction velocity increased in diabetic rats treated with ranirestat (43.3 ± 3.6 m/s) compared with rats treated with placebo (39.8 ± 2.3). Motor nerve conduction velocity also increased in the ranirestat group (45.6 ± 3.9) compared with the placebo group (38.9 ± 3.5). The foot withdrawal latency to noxious heating was improved in the ranirestat group (17.7 ± 0.6 seconds) compared with the placebo group (20.6 ± 0.6). The decrease in the intraepidermal fiber density was significant in the diabetic placebo group (21.6 ± 1.7/mm) but not significant in the diabetic ranirestat group (26.2 ± 1.2) compared with the nondiabetic placebo group (30.3 ± 1.5). Neurite outgrowth was promoted in the neurons supplemented with ranirestat (control 1446 ± 147 m/neuron, ranirestat 2175 ± 149). Ranirestat improved the peripheral nervous dysfunctions in rats with advanced diabetic polyneuropathy. Ranirestat could have potential for regeneration in the peripheral nervous system of diabetic rats.
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http://dx.doi.org/10.1155/2019/2756020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885776PMC
June 2020

Secreted factors from cultured dental pulp stem cells promoted neurite outgrowth of dorsal root ganglion neurons and ameliorated neural functions in streptozotocin-induced diabetic mice.

J Diabetes Investig 2020 Jan 21;11(1):28-38. Epub 2019 Jun 21.

Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.

Aims/introduction: Transplantation of stem cells promotes axonal regeneration and angiogenesis in a paracrine manner. In the present study, we examined whether the secreted factors in conditioned medium of stem cells from human exfoliated deciduous teeth (SHED-CM) had beneficial effects on diabetic polyneuropathy in mice.

Materials And Methods: Conditioned medium of stem cells from human exfoliated deciduous teeth was collected 48 h after culturing in serum-free Dulbecco's modified Eagle's medium (DMEM), and separated into four fractions according to molecular weight. Dorsal root ganglion neurons from C57BL/6J mice were cultured with SHED-CM or DMEM to evaluate the effect on neurite outgrowth. Streptozotocin-induced diabetic mice were injected with 100 μL of SHED-CM or DMEM into the unilateral hindlimb muscles twice a week over a period of 4 weeks. Peripheral nerve functions were evaluated by the plantar test, and motor and sensory nerve conduction velocities. Intraepidermal nerve fiber densities, capillary number-to-muscle fiber ratio, capillary blood flow and morphometry of sural nerves were also evaluated.

Results: Conditioned medium of stem cells from human exfoliated deciduous teeth significantly promoted neurite outgrowth of dorsal root ganglion neurons compared with DMEM. Among four fractions of SHED-CM, the only fraction of <6 kDa promoted the neurite outgrowth of dorsal root ganglion neurons. In addition, SHED-CM significantly prevented decline in sensory nerve conduction velocities compared with DMEM in diabetic mice. Although SHED-CM did not improve intraepidermal nerve fiber densities or morphometry of sural nerves, SHED-CM ameliorated the capillary number-to-muscle fiber ratio and capillary blood flow.

Conclusions: These results suggested that SHED-CM might have a therapeutic effect on diabetic polyneuropathy through promoting neurite outgrowth, and the increase in capillaries might contribute to the improvement of neural function.
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http://dx.doi.org/10.1111/jdi.13085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944849PMC
January 2020

Glucagon-Like Peptide-1 Receptor Agonist Protects Dorsal Root Ganglion Neurons against Oxidative Insult.

J Diabetes Res 2019 21;2019:9426014. Epub 2019 Feb 21.

Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.

Objective: Diabetic polyneuropathy (DPN) is one of the most prevalent diabetic complications. We previously demonstrated that exendin-4 (Ex4), a glucagon-like peptide-1 receptor agonist (GLP-1RA), has beneficial effects in animal models of DPN. We hypothesized that GLP-1 signaling would protect neurons of the peripheral nervous system from oxidative insult in DPN. Here, the therapeutic potential of GLP-1RAs on DPN was investigated in depth using the cellular oxidative insult model applied to the dorsal root ganglion (DRG) neuronal cell line.

Research Design And Methods: Immortalized DRG neuronal 50B11 cells were cultured with and without hydrogen peroxide in the presence or absence of Ex4 or GLP-1(7-37). Cytotoxicity and viability were determined using a lactate dehydrogenase assay and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt), respectively. Antioxidant enzyme activity was evaluated using a superoxide dismutase assay. Alteration of neuronal characteristics of 50B11 cells induced by GLP-1RAs was evaluated with immunocytochemistry utilizing antibodies for transient receptor potential vanilloid subfamily member 1, substance P, and calcitonin gene-related peptide. Cell proliferation and apoptosis were also examined by ethynyl deoxyuridine incorporation assay and APOPercentage dye, respectively. The neurite projection ratio induced by treatment with GLP-1RAs was counted. Intracellular activation of adenylate cyclase/cyclic adenosine monophosphate (cAMP) signaling was also quantified after treatment with GLP-1RAs.

Results: Neither Ex4 nor GLP-1(7-37) demonstrated cytotoxicity in the cells. An MTS assay revealed that GLP-1RAs amended impaired cell viability induced by oxidative insult in 50B11 cells. GLP-1RAs activated superoxide dismutase. GLP-1RAs induced no alteration of the distribution pattern in neuronal markers. Ex4 rescued the cells from oxidative insult-induced apoptosis. GLP-1RAs suppressed proliferation and promoted neurite projections. No GLP-1RAs induced an accumulation of cAMP.

Conclusions: Our findings indicate that GLP-1RAs have neuroprotective potential which is achieved by their direct actions on DRG neurons. Beneficial effects of GLP-1RAs on DPN could be related to these direct actions on DRG neurons.
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http://dx.doi.org/10.1155/2019/9426014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408997PMC
October 2019
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