Susumu Ikehara

Kansai Medical University, Moriguchi, Ōsaka, Japan

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Publications (435)1884.75 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone marrow-derived cells enter the brain in a non-inflammatory condition through the attachments of choroid plexus and differentiate into ramified myeloid cells. Neurodegenerative conditions may be associated with altered immune-brain interaction. The senescence-accelerated mouse prone 10 (SAMP10) undergoes earlier onset neurodegeneration than C57BL/6 (B6) strain. We hypothesized that the dynamics of immune cells migrating from the bone marrow to the brain is perturbed in SAMP10 mice. We created 4 groups of radiation chimeras by intra-bone marrow-bone marrow transplantation using 2-month-old (2 mo) and 10 mo SAMP10 and B6 mice as recipients with GFP transgenic B6 mice as donors, and analyzed histologically 4 months later. In the [B6 → 10 mo SAMP10] chimeras, more ramified marrow-derived cells populated a larger number of discrete brain regions than the other chimeras, especially in the diencephalon. Multiplex cytokine assays of the diencephalon prepared from non-treated 3 mo and 12 mo SAMP10 and B6 mice revealed that 12 mo SAMP10 mice exhibited higher tissue concentrations of CXCL1, CCL11, G-CSF, CXCL10 and IL-6 than the other groups. Immunohistologically, choroid plexus epithelium and ependyma produced CXCL1, while astrocytic processes in the attachments of choroid plexus expressed CCL11 and G-CSF. The median eminence produced CXCL10, hypothalamic neurons G-CSF and tanycytes CCL11 and G-CSF. These brain cytokine profile changes in 12 mo SAMP10 mice were likely to contribute to acceleration of the dynamics of marrow-derived cells to the diencephalon. Further studies on the functions of ramified marrow-derived myeloid cells would enhance our understanding of the brain-bone marrow interaction.
    Brain Structure and Function 01/2015; · 7.84 Impact Factor
  • Source
    Ming Li, Kequan Guo, Susumu Ikehara
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    ABSTRACT: Alzheimer's disease (AD) is a progressive and neurodegenerative disorder that induces dementia in older people. It was first reported in 1907 by Alois Alzheimer, who characterized the disease as causing memory loss and cognitive impairment. Pathologic characteristics of AD are β-amyloid plaques, neurofibrillary tangles and neurodegeneration. Current therapies only target the relief of symptoms using various drugs, and do not cure the disease. Recently, stem cell therapy has been shown to be a potential approach to various diseases, including neurodegenerative disorders, and in this review, we focus on stem cell therapies for AD.
    International Journal of Molecular Sciences 10/2014; 15(10):19226-19238. · 2.34 Impact Factor
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    Ming Li, Kuquan Guo, Susumu Ikehara
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    ABSTRACT: Bone marrow transplantation (BMT) is used to treat hematological disorders, autoimmune diseases (ADs) and lymphoid cancers. Intra bone marrow-BMT (IBM-BMT) has been proven to be a powerful strategy for allogeneic BMT due to the rapid hematopoietic recovery and the complete restoration of T cell functions. IBM-BMT not only replaces hematopoietic stem cells (HSCs) but also mesenchymal stromal cells (MSCs). MSCs are multi-potent stem cells that can be isolated from bone marrow (BM), umbilical cord blood (UCB), and adipose tissue. MSCs play an important role in the support of hematopoiesis, and modify and influence the innate and adaptive immune systems. MSCs also differentiate into mesodermal, endodermal and ectodermal lineage cells to repair tissues. This review aims to summarize the functions of BM-derived-MSCs, and the treatment of intractable diseases such as rheumatoid arthritis (RA) and malignant tumors with IBM-BMT.
    Frontiers in Cell and Developmental Biology 09/2014; 2:48.
  • Brain Behavior and Immunity 09/2014; 40:e17. · 6.13 Impact Factor
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    ABSTRACT: Other than that in the duodenum, adenocarcinoma in the small bowel is rare. The present study describes a case of adenocarcinoma with adenoma in the jejunum. A 70-year-old male was admitted to hospital due to dehydration induced by abdominal discomfort and difficulty with oral intake. Computed tomography revealed a tumor in the upper side of the jejunum, which was subsequently resected. The tumor contained adenocarcinoma and adenoma. The protein expression of p53 and Ki-67 was analyzed in the normal mucosa, adenoma and adenocarcinoma. The number of epithelial cells expressing p53 and Ki-67 was found to increase in the adenoma tissue compared with that in the normal mucosa. In the adenocarcinoma tissue, the number of cells expressing p53 and Ki-67 further increased, suggesting that an adenoma-adenocarcinoma sequence may occur in the small bowel, similar to that observed in the large bowel.
    Oncology letters 08/2014; 8(2):633-636. · 0.99 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of B-cell lymphoma characterized by selective growth of clonal B-cells in the lumen of the small vessels of various organs including the liver, spleen, lungs, skin, brain, and kidney. An 86-year-old male presented with weight loss, fever and night sweats (known as B symptoms). Blood examination revealed pancytopenia, high lactate dehydrogenase and high soluble interleukin-2 receptor, suggesting hematopoietic malignancy. However, there were no abnormal hematopoietic cells in the peripheral blood. No lymph node swelling was identified on examination by whole-body computed tomography scan. Therefore, IVLBCL was suspected, and random skin biopsies and a skin biopsy from a senile hemangioma were carried out. A small number of large atypical lymphoid cells resided in the small blood vessels in the deep dermis and subcutaneous tissue of the random skin biopsies, and numerous atypical lymphoid cells were identified in the small vessels of the senile hemangioma. These results suggest the usefulness of skin biopsy from senile hemangiomas in the diagnosis of IVLBCL.
    Oncology letters 06/2014; 7(6):2003-2006. · 0.99 Impact Factor
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    ABSTRACT: It has been shown that allogeneic intra-bone marrow-bone marrow transplantation (IBM-BMT) plus thymus transplantation (TT) is effective in treating recipients with malignant tumors. Although TT increases the percentage of T cells in the early term after BMT, the myeloid-derived suppressor cells (MDSCs) are still the dominant population. We used the Gr-1 Ab to deplete the granulocytic MDSCs (G-MDSCs) in tumor-bearing mice that had received BMT+TT. Two weeks after the BMT, the mice injected with Gr-1 Ab showed smaller tumors than those in the control group. In addition, Gr-1 Ab significantly increased the percentages and numbers of CD4+ and CD8+ T cells, and decreased the percentages and numbers of MDSCs and G-MDSCs. No side effects of the Gr-1 Ab on recipient or donor thymus were observed. These findings indicate that Gr-1 Ab administered after BMT+TT may enhance the effectiveness of tumor suppression.
    PLoS ONE 05/2014; 9(5):e97908. · 3.53 Impact Factor
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  • Source
    Susumu Ikehara, Ming Li
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    ABSTRACT: Aging is a complex process of damage accumulation, and has been viewed as experimentally and medically intractable. The number of patients with age-associated diseases such as type 2 diabetes mellitus (T2DM), osteoporosis, Alzheimer's disease (AD), Parkinson's disease, atherosclerosis, and cancer has increased recently. Aging-related diseases are related to a deficiency of the immune system, which results from an aged thymus and bone marrow cells. Intra bone marrow-bone marrow transplantation (IBM-BMT) is a useful method to treat intractable diseases. This review summarizes findings that IBM-BMT can improve and treat aging-related diseases, including T2DM, osteoporosis and AD, in animal models.
    Frontiers in Cell and Developmental Biology 05/2014; 2:16.
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    ABSTRACT: Pulmonary sclerosing hemangioma (SH) is an uncommon benign or low-grade malignant tumor. Multicentric SH and SH with lymph node metastasis have rarely been reported. The present report describes a case of pulmonary SH with lymph node metastasis in a middle-aged female. A nodule was found incidentally in the lower left lung. The patient underwent left lower pulmonary lobectomy and lymph node dissection. Histologically, the nodule demonstrated the characteristic features of SH and one of the resected lymph nodes contained a metastasis of this tumor. Thus, pulmonary SH has the potential to metastasize, a potential not suggested by histological features.
    Oncology letters 04/2014; 7(4):997-1000. · 0.99 Impact Factor
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    Ming Li, Susumu Ikehara
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    ABSTRACT: Type 1 diabetes mellitus (T1DM) is a common chronic disease in children, characterized by a loss of β cells, which results in defects in insulin secretion and hyperglycemia. Chronic hyperglycemia causes diabetic complications, including diabetic nephropathy, neuropathy, and retinopathy. Curative therapies mainly include diet and insulin administration. Although hyperglycemia can be improved by insulin administration, exogenous insulin injection cannot successfully mimic the insulin secretion from normal β cells, which keeps blood glucose levels within the normal range all the time. Islet and pancreas transplantation achieves better glucose control, but there is a lack of organ donors. Cell based therapies have also been attempted to treat T1DM. Stem cells such as embryonic stem cells, induced pluripotent stem cells and tissue stem cells (TSCs) such as bone marrow-, adipose tissue-, and cord blood-derived stem cells, have been shown to generate insulin-producing cells. In this review, we summarize the most-recently available information about T1DM and the use of TSCs to treat T1DM.
    Frontiers in Cell and Developmental Biology 03/2014; 2:9.
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    Kequan Guo, Susumu Ikehara, Xu Meng
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    ABSTRACT: Organ transplantation is useful for treating the end stage of organ failure. The induction of tolerance to the transplanted organ is essential for its long-term survival. Immunologic tolerance can be induced by immunosuppressive agents and mixed chimerism. Mixed chimerism is a state in which both recipient-and donor-derived blood cells remain in the hematopoietic system after allogeneic hematopoietic stem cells have been transplanted. Mesenchymal stem cells (MSCs), and immune cells such as dendritic cells and T-reg cells play an important role in the induction of tolerance. MSCs secrete cytokines, which modulate the immune response. In particular, they upregulate T-reg cell function and thereby induce tolerance. Intra-bone marrow-bone marrow transplantation recruits both donor-derived HSCs and MSCs, inducing persistent donor-specific tolerance without the use of immunosuppressants. In this review, we summarize the use of MSCs to induce tolerance in organ transplantation.
    Frontiers in Cell and Developmental Biology 03/2014; 2:8.
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    ABSTRACT: SKG/Jcl (SKG) mice spontaneously develop T cell-mediated autoimmune arthritis and may be an effective model for studying human rheumatoid arthritis. We sought to confirm that arthritis in SKG mice was caused by stem cell disorders. We induced systemic arthritis in normal C57/BL6 (B6) mice (H-2(b) type) by injecting lineage-negative (lin(-)) immature cells isolated from bone marrow cells (BMCs) of SKG mice (H-2(d) type) directly into bone cavities. Twenty weeks later, we analyzed arthritis scores, hematoxylin-eosin (H-E) staining and tartrate-resistant acid phosphatase (TRAP) staining in ankle joints, H-2 type of hematolymphoid and osteoblast-like cells, serum levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and percentages of CD4(+) T cells and osteoblast-like cells expressing receptor activator of nuclear factor kappa-B ligand (RANKL) in recipient mice. Donor-derived hematolymphoid cells and osteoblast-like cells had completely replaced donor-derived cells in the recipients (H-2(b) to H-2(d)). All recipients showed severe joint swelling with hyperemia and developed hypertrophic synovitis with lymphocytes accumulated around joints. All recipients also had higher TNF-α and IL-6 levels than untreated B6 controls. Furthermore, the percentages of CD4(+) T cells and osteoblast-like cells expressing RANKL and the number of TRAP(+) cells were greater in treated animals. Donor-derived hematolymphoid cells and osteoblast-like cells persisted in these recipients and promoted autoimmune arthritis and an increase in osteoclasts. Because autoimmune arthritis may be associated with abnormal lin(-) immature cells, patients with intractable autoimmune arthritis may be treated by replacing these cells with direct injection of lin(-) immature cells isolated from normal BMCs.
    Biological & Pharmaceutical Bulletin 01/2014; 37(11):1719-26. · 1.85 Impact Factor
  • Ming Li, Susumu Ikehara
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    ABSTRACT: Diabetes mellitus (DM) is a group of metabolic diseases in which a person has high blood glucose levels resulting from defects in insulin secretion and insulin action. The chronic hyperglycemia damages the eyes, kidneys, nerves, heart, and blood vessels. Curative therapies mainly include diet, insulin, and oral hypoglycemic agents. However, these therapies fail to maintain blood glucose levels in the normal range all the time. Although pancreas or islet-cell transplantation achieves better glucose control, a major obstacle is the shortage of donor organs. Recently, research has focused on stem cells which can be classified into embryonic stem cells (ESCs) and tissue stem cells (TSCs) to generate functional β cells. TSCs include the bone-marrow-, liver-, and pancreas-derived stem cells. In this review, we focus on treatment using bone marrow stem cells for type 1 and 2 DM.
    Journal of Diabetes Research 04/2013; 2013:329596. · 3.54 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Background/Aims: Minimal-change nephrotic syndrome (MCNS) is a kidney disease defined by selective proteinuria and hypoalbuminemia occurring in the absence of cellular glomerular infiltrates or immunoglobulin deposits. Recent observations suggest that nuclear factor κB (NF-κB) of podocyte is strongly associated with the development of proteinuria in MCNS. Dehydroxymethylepoxyquinomicin (DHMEQ) is a novel NF-κB inhibitor that potently inhibits DNA-binding activity of NF-κB, resulting in several therapeutic effects in various pathological conditions. We conducted this study to ask whether DHMEQ may ameliorate the nephrosis in mice induced by puromycin aminonucleoside (PAN), which is considered to be an animal model for MCNS. Methods/Results: Pretreatment with DHMEQ alleviated the proteinuria and reversed the serum abnormalities in mice nephrosis induced by 450 mg/kg of PAN. Increased serum interleukin-6 level in PAN-induced nephrosis was also completely suppressed by DHMEQ. Electron microscopic analyses of glo-meruli indicated that DHMEQ can inhibit the podocyte foot process effacement via blocking the translocation of podocyte NF-κB from cytoplasm to nucleus. Conclusions: These results suggest that DHMEQ can be a potential therapeutic agent for MCNS.
    American Journal of Nephrology 03/2013; 37(4):302-309. · 2.65 Impact Factor
  • Ming Li, Susumu Ikehara
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    ABSTRACT: Mesenchymal stem cells (MSCs) are prototypical adult stem cells with the capacity for self-renewal and differentiation with a broad tissue distribution. MSCs not only differentiate into types of cells of mesodermal lineage but also into endodermal and ectodermal lineages such as bone, fat, cartilage and cardiomyocytes, endothelial cells, lung epithelial cells, hepatocytes, neurons, and pancreatic islets. MSCs have been identified as an adherent, fibroblast-like population and can be isolated from different adult tissues, including bone marrow (BM), umbilical cord, skeletal muscle, and adipose tissue. MSCs secrete factors, including IL-6, M-CSF, IL-10, HGF, and PGE2, that promote tissue repair, stimulate proliferation and differentiation of endogenous tissue progenitors, and decrease inflammatory and immune reactions. In this paper, we focus on the role of BM-derived MSCs in organ repair.
    Stem cells international. 03/2013; 2013:132642.
    This article is viewable in ResearchGate's enriched format
  • Ming Li, Ming Shi, Nader G Abraham, Susumu Ikehara
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    ABSTRACT: Aging is accompanied by various forms of immune dysfunction, leading to an increase in frequency of infections and the development of malignant tumors in mice and humans. Sirt1 has been implicated in processes as varied as metabolism, differentiation, cancer, and the stress response and aging. Senescence accelerated mice prone 10 (SAMP10) show not only spontaneously-occurring brain atrophy, with deficits in learning and memory, but also emotional disorders. We attempted in this study to clarify the deficits and found that the percentage of CD4/TNFα T cells in the spleen of 24-wk-old (but not 6-wk-old) SAMP10 to be significantly reduced. The thymus was significantly lighter and the percentage of CD4⁺CD8⁺ cells was significantly lower in the 24-wk-old SAMP10 than 6-wk-old SAMP10. Microarray analyses indicated that genes related to transcription coactivator activity, growth factor activity, hormone activity and cytokine activity, receptor activity, and regulation of the immune system were downregulated in the thymus of 24-wk-old SAMP10. Real time PCR analysis showed that the expression of KGF, Aire and Sirt1 was decreased on the thymic epithelial cells (TECs) of 24-wk-old SAMP10. However, these parameters improved after the mice were treated with intra-bone marrow-bone marrow transplantation. This is the first report of age-related changes in immune system dysfunction in 24-wk-old SAMP10, and the first to show that dysfunction on the TECs of 24-wk-old SAMP10 was modulated by allogeneic bone marrow cells.
    Cell Transplantation 02/2013; · 3.57 Impact Factor
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    ABSTRACT: Thymus transplantation, in conjunction with bone marrow transplantation (BMT), has been attracting attention for the treatment of various diseases. Recently, donor lymphocyte infusion (DLI) has been used as a helpful tool for establishing donor chimerism and preventing a relapse of leukemia/lymphoma. However, the effects of DLI on transplanted and recipient thymuses have not been explored. We therefore performed DLI in the intrabone marrow-BMT + thymus transplantation setting. We have found that DLI leads to derangements in both recipient thymuses and transplanted thymuses; by 2 wk after BMT, we saw a decrease in total cell number, a lower percentage of CD4(+)CD8(+) cells, and the obliteration of the thymic corticomedullary junction. Four weeks later, the thymic impairment became more serious. However, when we depleted the CD4(+) T cells (CD4(-)-DLI), the recipient thymic recovery and transplanted thymic development were significantly restored by the treatment. In addition, there were much greater levels of TNF-α and Fas ligand, and a lower percentage of regulatory T cells in the DLI group than in the CD4(-)-DLI group. These findings indicate that inflammation induced by DLI, especially by CD4(+) T cells, plays a crucial role in the thymic impairment.
    The Journal of Immunology 02/2013; · 5.36 Impact Factor
  • Source
    Susumu Ikehara
    Frontiers in Cell and Developmental Biology 01/2013; 1:2.
  • Susumu Ikehara, Ming Shi, Ming Li
    Blood and Lymphatic Cancer: Targets and Therapy. 01/2013;
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    ABSTRACT: For immunodeficient patients, fungi are life-threatening pathogens. In this paper, we present an autopsy case of combined zygomycosis and aspergillosis. A female in her 70s on chronic hemodialysis was admitted to a hospital suffering bloody sputum, dyspnea, and fever, probably due to perinuclear anti-neutrophil cytoplasmic antibody-related vasculitis. Antibiotics were administered and immunosuppressive therapy was started, resulting in an improvement in her condition. Pneumonia later developed, followed by pulmonary bleeding and intractable pneumothorax from which she ultimately died. On autopsy, the upper lobe of the left lung was found to have hemorrhagic necrosis and showed a large longitudinal fissure. Microscopically, Zygomycota were observed in both the lungs and heart, while Aspergillus was found in the middle lobe of the right lung. Zygomycosis, which usually has a poor prognosis, is assumed to have induced hemorrhagic infarction of the lungs, inducing pulmonary bleeding and necrosis, despite the use of lipid formulations of amphotericin B, which are effective medicines against Zygomycota.
    International Journal of General Medicine 01/2013; 6:575-9.

Publication Stats

11k Citations
1,884.75 Total Impact Points

Institutions

  • 1987–2014
    • Kansai Medical University
      • • Department of Ophthalmology
      • • Department of Otolaryngology
      Moriguchi, Ōsaka, Japan
  • 2012
    • Aichi Human Service Center
      Касугай, Aichi, Japan
  • 2011
    • Nanfang Hospital
      Shengcheng, Guangdong, China
  • 2010
    • Fred Hutchinson Cancer Research Center
      • Division of Clinical Research
      Seattle, Washington, United States
  • 2004–2010
    • Osaka Prefecture University
      • Graduate School of Life and Environmental Sciences
      Sakai, Osaka-fu, Japan
  • 2002–2010
    • University of California, Davis
      • Division of Rheumatology/Allergy/Clinical Immunology
      Davis, California, United States
  • 2009
    • Medical University of Ohio at Toledo
      Toledo, Ohio, United States
  • 1984–2009
    • Kyoto University
      • • Department of Zoology
      • • Graduate School of Medicine / Faculty of Medicine
      • • Department of Cardiovascular Medicine
      • • Department of Dermatology
      Kioto, Kyōto, Japan
  • 2008
    • Università di Pisa
      • Department of Biology
      Pisa, Tuscany, Italy
    • Ibaraki Children's Hospital
      Ibaragi, Ōsaka, Japan
  • 2002–2008
    • New York Medical College
      • Department of Pharmacology
      New York City, New York, United States
    • Kyoto Institute of Technology
      Kioto, Kyōto, Japan
  • 1990–2004
    • Kyoto Prefectural University of Medicine
      • Graduate School of Medical Science
      Kioto, Kyōto, Japan
  • 1989–2002
    • University of South Florida St. Petersburg
      St. Petersburg, Florida, United States
  • 1994–1995
    • University of Ulsan
      • • Asan Medical Center
      • • College of Medicine
      Ulsan, Ulsan, South Korea
  • 1993
    • Osaka Red Cross Hospital
      Ōsaka, Ōsaka, Japan
  • 1991
    • All Children's Hospital
      Florida City, Florida, United States
    • Hokkaido University
      • Institute of Immunological Science
      Sapporo, Hokkaidō, Japan
  • 1981–1983
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States