Masayoshi Iwasaki

Publications of Masayoshi Iwasaki

• Modified resveratrol Longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment.

  Authors: Keisuke Fujitaka, Hajime Otani, Fusakazu Jo, Hiromi Jo, Emiko Nomura, Masayoshi Iwasaki, Mitsushige Nishikawa, Toshiji Iwasaka, Dipak K Das

  Nutrition research (New York, N.Y.). 11/2011; 31(11):842-7.

  Resveratrol is known to improve endothelial function in animals, but little is known about its effect on human subjects. Metabolic syndrome (MetS) is a cluster of cardiovascular risk factorsResveratrol is known to improve endothelial function in animals, but little is known about its effect on human subjects. Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors underlying endothelial dysfunction. We hypothesized that the modified resveratrol, Longevinex, improves endothelial function in patients with MetS. Thirty-four patients who had been treated for MetS and lifestyle-related disease were randomly assigned to group A, in which Longevinex was administered for 3 months and then discontinued for 3 months, whereas in the time-matched group B, Longevinex was administered between 3 and 6 months. These 2 groups of patients received similar drugs at baseline for diabetes mellitus, dyslipidemia, or hypertension. Flow-mediated dilatation significantly increased during the administration of Longevinex but decreased to baseline 3 months after the discontinuation of Longevinex in the group A patients. Conversely, in the group B patients, flow-mediated dilatation remained unchanged for the first 3 months without Longevinex but was significantly increased 3 months after the treatment with Longevinex. Longevinex did not significantly affect blood pressure, insulin resistance, the lipid profile or inflammatory markers during 6-month follow-up. These results demonstrate that Longevinex specifically improves endothelial function in subjects with MetS who were receiving standard therapy for lifestyle-related disease.

• Comparison of metabolic profile and adiponectin level with pioglitazone versus voglibose in patients with type-2 diabetes mellitus associated with metabolic syndrome.

  Authors: Keisuke Fujitaka, Hajime Otani, Fusakazu Jo, Hiromi Jo, Emiko Nomura, Masayoshi Iwasaki, Mitsushige Nishikawa, Toshiji Iwasaka

  Endocrine journal. 04/2011; 58(6):425-32.

  Type 2 diabetes mellitus (T2DM) associated with metabolic syndrome (MetS) represents a high risk of cardiovascular disease. We compared the effect of early intervention with pioglitazone versusType 2 diabetes mellitus (T2DM) associated with metabolic syndrome (MetS) represents a high risk of cardiovascular disease. We compared the effect of early intervention with pioglitazone versus voglibose on physical and metabolic profiles and serum adiponectin level in patients with T2DM associated with MetS. Sixty patients who were diagnosed for the first time as T2DM associated with MetS were analyzed for insulin sensitivity, lipid profile, serum adiponectin and systemic inflammation. Those patients were randomly assigned to oral pioglitazone group (n = 30) or voglibose group (n = 30) in addition to conventional diet and exercise training. Body mass index and waist circumference did not change in the pioglitazone group, whereas these physical parameters significantly decreased in the voglibose group during a 6-month follow-up period. However, glycosylated hemoglobin, fasting plasma glucose, and HOMA-IR more significantly decreased in the pioglitazone group. The level of serum adiponectin especially high-molecular weight adiponectin markedly increased in the pioglitazone group. Moreover, high sensitive CRP significantly decreased only in the pioglitazone group. These results suggest that voglibose is superior in improving obesity, while pioglitazone is superior in ameliorating insulin sensitivity and increasing serum adiponectin in patients with an early stage of T2DM associated with MetS.

• Signaling from fibroblast growth factor receptor 2 in immature hematopoietic cells facilitates donor hematopoiesis after intra-bone marrow-bone marrow transplantation.

  Authors: Akio Shigematsu, Ming Shi, Mitsuhiko Okigaki, Yasushi Adachi, Naoko Koike, Jishan Che, Masayoshi Iwasaki, Hiroaki Matsubara, Masahiro Imamura, Susumu Ikehara

  Stem cells and development. 03/2010; 19(11):1679-86.

  Fibroblast growth factor (FGF) and FGF receptor (FGFR) are expressed in various cells including endothelial progenitor cells and hematopoietic cells. The interaction between FGF and FGFR isFibroblast growth factor (FGF) and FGF receptor (FGFR) are expressed in various cells including endothelial progenitor cells and hematopoietic cells. The interaction between FGF and FGFR is associated with the proliferation, migration, and survival of these cells. In this report, we examined the effects of FGFR2 signaling on hematopoiesis in immature hematopoietic cells, using mutant mice in which a constitutively active form of FGFR2 mutant was caused to be overexpressed by the Tie2 promoter (FGFR2 Tg mice). Under normal conditions, hematopoiesis of FGFR2 Tg mice and wild type (Wt) mice do not differ significantly, except for the weight and cell numbers of the thymus. However, the c-kit(+)Sca-1(+)lineage⁻ bone marrow cells (BMCs) of FGFR2 Tg mice facilitate the formation of colony-forming units of culture. When these BMCs were transplanted into the recipient bone marrow (intra-bone marrow-bone marrow transplantation), there was better reconstitution of donor hematopoietic cells. In the in vitro experiment, the c-kit(+)Sca-1(+)lineage⁻ BMCs from FGFR2 Tg mice showed fewer apoptotic cells than those from Wt mice. These results suggest that the antiapoptotic effect of FGFR2 signaling facilitates the hematopoiesis of FGFR2 Tg mice.

• FKBP51 expressed by both normal epithelial cells and adenocarcinoma of colon suppresses proliferation of colorectal adenocarcinoma.

  Authors: Hiromi Mukaide, Yasushi Adachi, Shigeru Taketani, Masayoshi Iwasaki, Naoko Koike-Kiriyama, Akio Shigematsu, Ming Shi, Seiji Yanai, Kazuhiko Yoshioka, Yasuo Kamiyama, Susumu Ikehara

  Cancer investigation. 06/2008; 26(4):385-90.

  It has been reported, as a result of Western blot analyses, that FKBP51 is expressed in various tissues, but that it is not expressed in the pancreas, lung, colon, stomach, or spleen. In this paper,It has been reported, as a result of Western blot analyses, that FKBP51 is expressed in various tissues, but that it is not expressed in the pancreas, lung, colon, stomach, or spleen. In this paper, we show, using Western blot analyses, reverse transcriptase polymerase chain reaction, and immunohistochemical analyses of samples from colon cancer patients, that both normal epithelial cells and adenocarcinoma in the human colon express FKBP51, and that there are no significant differences in the expressions of FKBP51 between them. We also show that FKBP51 suppresses the proliferation of colorectal adenocarcinoma, possibly due to the suppression of functions of the glucocorticoid receptors.

• Administration of granulocyte colony-stimulating factor to recipients followed by intra-bone marrow-bone marrow transplantation accelerates acceptance of allogeneic bone marrow cells in mice.

  Authors: Yasuhiro Suzuki, Yasushi Adachi, Yuming Zhang, Keizo Minamino, Masayoshi Iwasaki, Hiromi Mukaide, Ming Shi, Keiji Nakano, Yasushi Koike, Jianfeng Wang, Naoko Koike-Kiriyama, Akio Shigematsu, Seiji Yanai, Susumu Ikehara

  Immunobiology. 02/2008; 213(5):427-35.

  We have recently established a novel method for bone marrow transplantation: intra-bone marrow-bone marrow transplantation (IBM-BMT), by which the rapid recovery of donor-derived hematopoiesis can beWe have recently established a novel method for bone marrow transplantation: intra-bone marrow-bone marrow transplantation (IBM-BMT), by which the rapid recovery of donor-derived hematopoiesis can be expected even when reduced radiation doses are used. In this paper, we examine, using mice, whether the combination of pretreatment of recipients with granulocyte-colony-stimulating factor (G-CSF) and IBM-BMT can induce a more rapid recovery of donor-derived hematopoiesis than IBM-BMT alone. We first pretreated recipients with recombinant human (rh) G-CSF (250mug/kg/day) for 5 consecutive days (days -6 to -2). On day -1, the recipients were irradiated, and IBM-BMT was carried out on day 0. On day 12, we performed colony-forming units of spleen (CFU-S) assays. The combination of G-CSF pretreatment and IBM-BMT augmented the CFU-S counts, the weight of spleens, and the numbers of donor-derived hematopoietic cells. We next analyzed the mechanisms underlying these effects of G-CSF and found that (i) G-CSF induces Th2 polarization, which can prevent graft rejection, and (ii) G-CSF augments natural suppressor activity, which suppresses graft rejection. The combination of G-CSF pretreatment and IBM-BMT can produce the rapid recovery of donor-derived hematopoiesis and suppress graft rejection. This method would lighten the burden on patients in allogeneic BMT.

• Immunotherapy for malignant tumors using combination of allogeneic intra-bone marrow-bone marrow transplantation, donor lymphocyte infusion and dendritic cells.

  Authors: Hiromi Mukaide, Yasushi Adachi, Naoko Koike-Kiriyama, Yasuhiro Suzuki, Keizo Minamino, Masayoshi Iwasaki, Masanobu Tsuda, Keiji Nakano, Yasushi Koike, Akio Shigematsu, Yasuo Kamiyama, Susumu Ikehara

  International journal of oncology. 07/2007; 30(6):1309-15.

  We have previously shown that the combination of allogeneic intra-bone marrow-bone marrow transplantation (IBM-BMT) and donor lymphocyte infusion (DLI) using CD4+ cell-depleted spleen cells isWe have previously shown that the combination of allogeneic intra-bone marrow-bone marrow transplantation (IBM-BMT) and donor lymphocyte infusion (DLI) using CD4+ cell-depleted spleen cells is effective in suppressing tumor growth, but that this does not induce graft-versus-host disease (GVHD) in mice. In this report, we show that formalin-fixed tumor cell-pulsed dendritic cells (FFTCP DCs) have an additive effect with IBM-BMT plus DLI on the suppression of tumor growth, but that the DCs do not augment GVHD. BALB/c mice, which had been subcutaneously inoculated with Meth A (BALB/c-derived fibrosarcoma), were irradiated at a low dose (5 Gy) and were transplanted with bone marrow cells (BMCs) from C57BL/6 (B6) mice into the bone marrow cavity (IBM-BMT). Simultaneously, the mice were intravenously injected with spleen cells from B6 mice, and subcutaneously injected with FFTCP DCs derived from the bone marrow (BM) of B6 mice. At the point of the induction of DCs from BMCs, formalin-fixed Meth A cells were added into the culture. The mice treated with the combination of FFTCP DCs, IBM-BMT and DLI using CD4+ cell-depleted spleen cells showed smaller tumor sizes and longer survival than the mice treated with IBM-BMT plus FFTCP DCs or IBM-BMT plus DLI using CD4+ cell-depleted spleen cells. These results suggest that the combination of FFTCP DCs, IBM-BMT plus DLI using CD4+ cell-depleted spleen cells has potent anti-tumor effects without showing GVHD.

• Allogeneic intrabone marrow-bone marrow transplantation plus donor lymphocyte infusion suppresses growth of colon cancer cells implanted in skin and liver of rats.

  Authors: Yasushi Koike, Yasushi Adachi, Yasuhiro Suzuki, Masayoshi Iwasaki, Naoko Koike-Kiriyama, Keizo Minamino, Keiji Nakano, Hiromi Mukaide, Akio Shigematsu, Yasuhiko Kiyozuka, Airo Tubura, Yasuo Kamiyama, Susumu Ikehara

  Stem cells (Dayton, Ohio). 03/2007; 25(2):385-91.

  We have recently found that allogeneic intrabone marrow-bone marrow transplantation (IBM-BMT) + donor lymphocyte infusion (DLI) using CD4(+) cell-depleted spleen cells (CD4(-) cells) can preventWe have recently found that allogeneic intrabone marrow-bone marrow transplantation (IBM-BMT) + donor lymphocyte infusion (DLI) using CD4(+) cell-depleted spleen cells (CD4(-) cells) can prevent graft-versus-host disease (GvHD) but suppress tumor growth (Meth A: fibrosarcoma) in mice. In the present study, we show that allogeneic IBM-BMT + DLI using CD4(-) cells also has suppressive effects on the growth of colon cancer cells implanted not only in the skin but also in the liver of rats. First, we examined the effects of allogeneic IBM-BMT + DLI on the subcutaneously inoculated ACL-15 (rat colon cancer cell line). Lethally irradiated Fischer rats (F344 rats) were transplanted with T-cell-depleted bone marrow cells (BMCs) from Brown Norway (BN) rats. Simultaneously, DLI was performed using whole spleen cells (whole cells), CD4(+) cell-depleted spleen cells (CD4(-) cells) or CD8(+) cell-depleted spleen cells (CD8(-) cells) of BN rats. Although allogeneic IBM-BMT + DLI suppressed tumor growth, a considerable number of rats treated with allogeneic IBM-BMT + DLI using whole cells or CD8(-) cells died due to GvHD. In contrast, allogeneic IBM-BMT + DLI using CD4(-) cells also suppressed tumor growth, but there was no GvHD. Based on these findings, we next examined the effects of allogeneic IBM-BMT + DLI using CD4(-) cells on the cancer cells implanted in the liver. Allogeneic IBM-BMT + DLI using CD4(-) cells via the portal vein significantly prolonged the survival. These results suggest that allogeneic IBM-BMT + DLI using CD4(-) cells could become a new strategy for the treatment of solid tumors.

• An innovative approach to bone marrow collection and transplantation in a patient with beta-thalassemia major: marrow collection using a perfusion method followed by intra-bone marrow injection of collected bone marrow cells.

  Authors: Chunfu Li, Yuelin He, Xiaoqin Feng, Muneo Inaba, Yasushi Adachi, Keizo Takada, Yuming Zhang, Yoshihisa Yamamoto, Xuedong Wu, Yunze Cui [......] Naoki Hosaka, Mitsuru Taira, Keizo Minamino, Yasuhiro Suzuki, Keiji Nakano, Junichi Fukui, Yusuke Ueda, Yasushi Koike, Masanobu Tsuda, Susumu Ikehara

  International journal of hematology. 02/2007; 85(1):73-7.

  Using small animals (mice and rats) and monkeys, we have found that the combination of bone marrow collection using the perfusion method (PM) and intra-bone marrow-bone marrow transplantationUsing small animals (mice and rats) and monkeys, we have found that the combination of bone marrow collection using the perfusion method (PM) and intra-bone marrow-bone marrow transplantation (IBM-BMT) of the collected cells is safe and effective in treating various intractable diseases. Based on these findings, we attempted to apply this method to humans. We report here the first case of a patient (6 years old) with beta-thalassemia major who underwent allogeneic BMT using this new PM + IBM-BMT method. The white blood cell counts of the patient gradually increased to more than 1500/microL by day 47 and continued to increase, reaching the highest level (8600/microL) on day +55. Fluorescence in situ hybridization data on day +33 showed that 98% of the peripheral blood cells were from the donor. Notably, there were no symptoms of graft-versus-host disease (GvHD). However, on day +56, the patient regrettably died of asphyxia resulting from sticky sputum. There was no evidence of infection (in the lung or liver) or GvHD (in the skin) by necropsy. We hope that this case report will help make our new strategies more readily available for the treatment of patients with various intractable diseases.

• Effects of low-dose irradiation on enhancement of immunity by dendritic cells.

  Authors: Akio Shigematsu, Yasushi Adachi, Naoko Koike-Kiriyama, Yasuhiro Suzuki, Masayoshi Iwasaki, Yasushi Koike, Keiji Nakano, Hiromi Mukaide, Masahiro Imamura, Susumu Ikehara

  Journal of radiation research. 02/2007; 48(1):51-5.

  Low-doses of irradiation have been reported to have beneficial effects, particularly anti-tumor effects. In this paper, we show the effects of the low-dose irradiation on T cell activation induced byLow-doses of irradiation have been reported to have beneficial effects, particularly anti-tumor effects. In this paper, we show the effects of the low-dose irradiation on T cell activation induced by dendritic cells (DCs). DCs, which had been pre-irradiated at 0.02-1.0 Gy from a (137)Cs source, were cultured with allogeneic T cells, and the proliferation of T cells was then examined. The 0.05Gy-pre-irradiated DCs showed the highest proliferation capacity of T cells. The 0.05Gy-irradiation does not augment the expression of major histocompatibility complexes (MHCs) or costimulatory molecules on DCs, as with non-irradiated DCs or 1Gy-irradiated DCs, but does augment the production of IL-2, IL-12 and IFN-gamma DCs. These results suggest that the low-dose irradiation augments T cell-activation capacity through cytokine production by DCs, which might shift naïve helper T cells to Th1 cells.

• Human cord blood cells can differentiate into retinal nerve cells.

  Authors: Naoko Koike-Kiriyama, Yasushi Adachi, Keizo Minamino, Masayoshi Iwasaki, Keiji Nakano, Yasushi Koike, Haruhiko Yamada, Hiromi Mukaide, Akio Shigematsu, Tomomi Mizokami, Miyo Matsumura, Susumu Ikehara

  Acta neurobiologiae experimentalis. 02/2007; 67(4):359-65.

  Retinal degeneration and dystrophy are the major causes of blindness in the developed world. It has been reported that human cord blood cells (HCBCs) can differentiate into neuron-like cells inRetinal degeneration and dystrophy are the major causes of blindness in the developed world. It has been reported that human cord blood cells (HCBCs) can differentiate into neuron-like cells in vitro. We have recently demonstrated that bone marrow cells (BMCs) of both mice and rats can differentiate into retinal nerve cells (RNCs). In the present study, we show the differentiation capacity of HCBCs into RNCs in vivo. We transplanted lineage-negative HCBCs into the subretinal space of severe combined immunodeficiency (SCID) mice. Two weeks after the transplantation, some of the transplanted cells expressed human nestin, human MAP2, human neuron specific enolase (NSE), beta-III tubulin and also rhodopsin. These results indicate that HCBCs can differentiate into RNCs and suggest that our new strategy could be used for the regeneration of retinal nerve cells in degenerative or dystrophic diseases.

• Treatment and transfer of emphysema by a new bone marrow transplantation method from normal mice to Tsk mice and vice versa.

  Authors: Yasushi Adachi, Haruki Oyaizu, Shigeru Taketani, Keizo Minamino, Kazuyuki Yamaguchi, Leonard D Shultz, Masayoshi Iwasaki, Minoru Tomita, Yasuhiro Suzuki, Keiji Nakano, Yasushi Koike, Ryoji Yasumizu, Makoto Sata, Noriyuki Hirama, Isao Kubota, Shirou Fukuhara, Susumu Ikehara

  Stem cells (Dayton, Ohio). 10/2006; 24(9):2071-7.

  We have recently established a new bone marrow transplantation (BMT) method in which bone marrow cells are injected into the intrabone marrow (IBM). In the present study, we used an animal model forWe have recently established a new bone marrow transplantation (BMT) method in which bone marrow cells are injected into the intrabone marrow (IBM). In the present study, we used an animal model for emphysema (tight-skin [Tsk] mouse) to examine whether IBM-BMT could be used to treat emphysema in Tsk mice. IBM-BMT was carried out from C3H mice into Tsk mice (8-10 weeks old) that had already shown emphysema. Six months after transplantation, the lungs of all the Tsk mice treated with IBM-BMT [C3H-->Tsk] showed similar structures to those of normal mice, whereas the [Tsk-->Tsk] mice showed emphysema, as seen in age-matched Tsk mice. Next, we attempted to transfer emphysema from Tsk mice to C3H mice by IBM-BMT. Six months after IBM-BMT, the [Tsk-->C3H] mice showed emphysema. These results strongly suggest that emphysema in Tsk mice originates from defects of stem cells in the bone marrow.

• Synergistic effects of granulocyte-colony stimulating factor and macrophage-colony stimulating factor on recovery of donor hematopoietic cells in allogeneic bone marrow transplantation.

  Authors: Yuming Zhang, Yasushi Adachi, Yasuhiro Suzuki, Keizo Minamino, Masayoshi Iwasaki, Keiji Nakano, Yasushi Koike, Hiromi Mukaide, Akio Shigematsu, Naoko Kiriyama, Chunfu Li, Susumu Ikehara

  Oncology reports. 09/2006; 16(2):367-71.

  G-CSF and M-CSF are used clinically to augment hematopoiesis after bone marrow transplantation (BMT) and chemotherapy. In this paper, we examined the synergistic effect of G-CSF and M-CSF onG-CSF and M-CSF are used clinically to augment hematopoiesis after bone marrow transplantation (BMT) and chemotherapy. In this paper, we examined the synergistic effect of G-CSF and M-CSF on hematopoietic recovery in allogeneic BMT as a model of human BMT. We performed BMT from eGFP-transgenic mice (C57BL/6 background; H-2b) into lethally-irradiated C3H (H-2k). From the day after BMT, G-CSF and/or M-CSF were injected for 5 consecutive days. Not only the numbers of day 12 CFU-S and spleen weight, but also white blood cell (WBC) counts in the peripheral blood (PB) and nuclear cells in the bone marrow (BM) increased in the mice treated with G-CSF and/or M-CSF 12 days after BMT. Moreover, the number of donor-type WBCs in the PB and donor-type nuclear cells in the BM also increased in the mice treated with G-CSF and/or M-CSF. The effects were pronounced when G-CSF and M-CSF were used together rather than independently. These results suggest that treatment with the combination of G-CSF and M-CSF has a synergistic effect on hematopoiesis in allogeneic BMT.

• G-CSF and/or M-CSF accelerate differentiation of bone marrow cells into endothelial progenitor cells in vitro.

  Authors: Yuming Zhang, Yasushi Adachi, Masayoshi Iwasaki, Keizo Minamino, Yasuhiro Suzuki, Keiji Nakano, Yasushi Koike, Hiromi Mukaide, Akio Shigematsu, Naoko Kiriyama, Chunfu Li, Susumu Ikehara

  Oncology reports. 07/2006; 15(6):1523-7.

  It has been reported that granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF) can mobilize endothelial progenitor cells (EPCs) in bone marrowIt has been reported that granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF) can mobilize endothelial progenitor cells (EPCs) in bone marrow cells (BMCs) into peripheral blood (PB) in vivo. Previously, we also reported that macrophage-colony stimulating factor (M-CSF) can mobilize EPCs into PB, which results in the rapid recovery of blood flow in induced-ischemia limbs by augmenting the number of intramuscular capillaries in vivo. In the present study, we demonstrate that M-CSF and/or G-CSF can increase EPCs from lineage (CD3, B220, Gr-1, Mac-1, CD11c, Ter119, NK1.1 or CD31)-negative BMCs in vitro. Lineage-negative BMCs were cultured with or without M-CSF and/or G-CSF. Three days after culture with M-CSF and/or G-CSF, the number of Flk-1+/CD45-, Sca-1+/CD45-, CD31+/CD45- or CD146+/CD45- cells increased in comparison with no cytokines. When the cultured BMCs with or without G-CSF and/or M-CSF were intravenously injected into ischemia-induced hindlimbs of mice, the number of intramuscular capillaries in the ischemia-induced legs increased; BMCs cultured with G-CSF and/or M-CSF were more effective than those of cytokine non-treated BMCs. These results suggest that M-CSF and/or G-CSF can induce the differentiation of BMCs into EPCs, even in vitro.

• Mechanisms underlying acceleration of blood flow recovery in ischemic limbs by macrophage colony-stimulating factor.

  Authors: Keiji Nakano, Yasushi Adachi, Keizo Minamino, Masayoshi Iwasaki, Akio Shigematsu, Naoko Kiriyama, Yasuhiro Suzuki, Yasushi Koike, Hiromi Mukaide, Shoichiro Taniuchi, Yohnosuke Kobayashi, Kazunari Kaneko, Susumu Ikehara

  Stem cells (Dayton, Ohio). 06/2006; 24(5):1274-9.

  Recently we reported that macrophage colony-stimulating factor (M-CSF) can mobilize endothelial progenitor cells (EPCs) from the bone marrow into the peripheral blood, resulting in an increase in theRecently we reported that macrophage colony-stimulating factor (M-CSF) can mobilize endothelial progenitor cells (EPCs) from the bone marrow into the peripheral blood, resulting in an increase in the number of blood vessels and augmentation of blood flow in the ischemia-induced legs. M-CSF accelerates neovascularization of ischemic lesions resulting from the mobilization of EPCs. In the present paper, we analyze the mechanisms underling the mobilization of EPCs by M-CSF. M-CSF augments the production of vascular endothelial growth factor (VEGF) from the bone marrow cells, especially from myeloid lineage cells. In vivo administration of anti-VEGF antibody abrogates both the acceleration of the recovery of blood flow in the ischemia-induced limbs by M-CSF and the augmentation of the mobilization of EPCs induced by M-CSF. These results suggest that the M-CSF contributes to rapid recovery of blood flow in ischemic lesions by mobilization of EPCs from the bone marrow through augmentation of VEGF production in the bone marrow and that the VEGF is mainly produced by myeloid lineage cells.

• Long-term observation after simultaneous lung and intra-bone marrow-bone marrow transplantation.

  Authors: Hiroyuki Kaneda, Yasushi Adachi, Yukihito Saito, Kazuya Ikebukuro, Hirohisa Machida, Yasuhiro Suzuki, Keizo Minamino, Yuming Zhang, Masayoshi Iwasaki, Keiji Nakano, Yasushi Koike, Jianfeng Wang, Hiroji Imamura, Susumu Ikehara

  The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 10/2005; 24(9):1415-23.

  BACKGROUND: Although lung transplantation is now an established treatment for end-stage lung diseases, allogeneic transplantation of parenchymal organs requires immunosuppressive therapy to preventBACKGROUND: Although lung transplantation is now an established treatment for end-stage lung diseases, allogeneic transplantation of parenchymal organs requires immunosuppressive therapy to prevent rejection. It has been reported that bone marrow transplantation (BMT) induces specific tolerance to donor organs. We have recently discovered a new method for BMT, which is called intra-bone marrow (IBM) BMT, in which bone marrow cells (BMCs) are injected directly into the bone marrow cavity. We demonstrate that IBM-BMT can be used to induce tolerance even in simultaneous lung transplantations in rats without administering any immunosuppressants. METHODS: Allogeneic lung transplantation was carried out from Brown Norway to Lewis rats. Simultaneously, IBM-BMT was carried out. RESULTS: Transplantation of nonirradiated lung or nontreated BMCs (T cell-containing BMCs) induced graft vs host disease. Therefore, the donor lung was irradiated, and T cells in the BMCs were depleted by anti-CD4, anti-CD5, and anti-CD8 antibodies plus anti-mouse antibody-coated magnetic beads. Lung allografts with conventional (intravenous) BMT failed to induce tolerance. However, the recipients treated with lung allografts plus IBM-BMT, which showed either mixed chimerism or full chimerism of hematopoietic cells, did not show symptoms of graft rejection or graft vs host disease, even without the use of immunosuppressants. CONCLUSIONS: These results suggest that simultaneous lung transplantation and IBM-BMT (but not conventional BMT) is effective in inducing persistent tolerance without the use of immunosuppressants.

• Long-term survival of bone marrow-derived retinal nerve cells in the retina.

  Authors: Keizo Minamino, Yasushi Adachi, Haruhiko Yamada, Akiko Higuchi, Yasuhiro Suzuki, Masayoshi Iwasaki, Keiji Nakano, Yasushi Koike, Hiromi Mukaide, Naoko Kiriyama, Akio Shigematsu, Miyo Matsumura, Susumu Ikehara

  Neuroreport. 09/2005; 16(12):1255-9.

  Recently, we have demonstrated that bone marrow stem cells can differentiate into retinal nerve cells. In the present study, we show a new and efficient strategy for transplanting bone marrow stemRecently, we have demonstrated that bone marrow stem cells can differentiate into retinal nerve cells. In the present study, we show a new and efficient strategy for transplanting bone marrow stem cells into the retina. When bone marrow stem cells were injected into the vitreous cavity of untreated eyes, only very few cells were found in the retina 2 weeks after injection. In contrast, when laser photocoagulation was performed just before the injection of bone marrow stem cells, a large number of the injected cells survived 2 weeks after injection and the cells expressed neural cell-specific or retinal nerve cell-specific antigens. Moreover, we still detected bone marrow stem cell-derived retinal nerve cells in the retina 1 year after injection in the retina.

• Autopsy case of primary choriocarcinoma of the urinary bladder.

  Authors: Keizo Minamino, Yasushi Adachi, Akiharu Okamura, Taketoshi Kushida, Motohiko Sugi, Masato Watanabe, Kouei Muguruma, Hideki Sugao, Yasuhiro Suzuki, Masayoshi Iwasaki, Keiji Nakano, Yasushi Koike, Jianfeng Wang, Hiromi Mukaide, Yuming Zhang, Tadashi Matsuda, Miyo Matsumura, Susumu Ikehara

  Pathology international. 05/2005; 55(4):216-22.

  Choriocarcinomas usually develop in the uterus and ovaries in the female, being extremely rare in the extragenital organs in the male. Extragenital choriocarcinomas in the male usually develop in theChoriocarcinomas usually develop in the uterus and ovaries in the female, being extremely rare in the extragenital organs in the male. Extragenital choriocarcinomas in the male usually develop in the mediastinum or retroperitoneum. The frequency of choriocarcinoma in the urinary bladder is extremely low. The purpose of the present paper was to report an autopsy case of choriocarcinoma in the urinary bladder in the male. An 81-year-old male patient with macrohematuria was first diagnosed with transitional cell carcinoma (TCC). At autopsy a hemorrhagic necrotic tumor, which was found in the urinary bladder with metastatic lesions in the lungs, was diagnosed as choriocarcinoma microscopically. There was no evidence for choriocarcinoma derived from any other organs than the urinary bladder, although there were metastatic lesions in both lungs and the direct invasion into the prostate. From these findings it is concluded that the tumor was a primary choriocarcinoma in the urinary bladder in a male patient. Choriocarcinoma of the urinary bladder is very rare, but the prognosis is extremely poor in comparison with TCC even in the urinary bladder. Therefore, it is essential to clearly discriminate between choriocarcinomas and TCC.

• Mobilization of bone marrow cells by G-CSF rescues mice from cisplatin-induced renal failure, and M-CSF enhances the effects of G-CSF.

  Authors: Masayoshi Iwasaki, Yasushi Adachi, Keizo Minamino, Yasuhiro Suzuki, Yuming Zhang, Mitsuhiko Okigaki, Keiji Nakano, Yasushi Koike, Jianfeng Wang, Hiromi Mukaide, Shigeru Taketani, Yasukiyo Mori, Hakuo Takahashi, Toshiji Iwasaka, Susumu Ikehara

  Journal of the American Society of Nephrology : JASN. 04/2005; 16(3):658-66.

  Cisplatin, which is a broadly used anticancer drug, is widely known to induce acute renal failure as a result of renal tubular injury. This article examines whether G-CSF and/or M-CSF rescues miceCisplatin, which is a broadly used anticancer drug, is widely known to induce acute renal failure as a result of renal tubular injury. This article examines whether G-CSF and/or M-CSF rescues mice from renal failure induced by cisplatin. BALB/c mice received intraperitoneal injections with or without G-CSF and/or M-CSF for 5 d (from day -5 to day -1). The day after the last injection of G-CSF and/or M-CSF (day 0), the mice received an intraperitoneal injection of cisplatin. When pretreated with G-CSF or G-CSF + M-CSF, the mice showed longer survival and lower serum creatinine and blood urea nitrogen levels than mice that had been received injections of M-CSF or saline. Histologically, pretreatment with G-CSF or G-CSF + M-CSF attenuated the damage to renal tubules induced by cisplatin. BALB/c mice that had received a transplant of bone marrow cells of enhanced green fluorescent protein (EGFP)-transgenic mice ([EGFP-->BALB/c] mice) were treated with or without G-CSF and/or M-CSF, followed by injection of cisplatin as well as above. [EGFP-->BALB/c] mice that were treated with G-CSF or G-CSF + M-CSF showed a significantly higher number of EGFP(+) tubular epithelial cells in the kidney than mice that were treated with only M-CSF or saline. These results suggest that bone marrow cells mobilized by G-CSF accelerate the improvement in renal functions and prevent the renal tubular injury induced by cisplatin and that M-CSF enhances the effects of G-CSF.

• The effect of residential exercise training on baroreflex control of heart rate and sympathetic nerve activity in patients with acute myocardial infarction.

  Authors: Jun Mimura, Fumio Yuasa, Reisuke Yuyama, Akihiro Kawamura, Masayoshi Iwasaki, Tetsuro Sugiura, Toshiji Iwasaka

  Chest. 04/2005; 127(4):1108-15.

  STUDY OBJECTIVES: Exercise training has been shown to favorably affect the prognosis after acute myocardial infarction (AMI), but the mechanisms of such favorable effects remain speculative. The aimSTUDY OBJECTIVES: Exercise training has been shown to favorably affect the prognosis after acute myocardial infarction (AMI), but the mechanisms of such favorable effects remain speculative. The aim of this study was to determine whether exercise training improves baroreflex control of heart rate and muscle sympathetic nerve activity (MSNA) in patients with AMI. DESIGN: Prospective randomized clinical study. PARTICIPANTS: Thirty patients with an uncomplicated AMI were randomized into trained or untrained groups. Arterial BP, heart rate, and MSNA were measured at rest, and during baroreceptor stimulation (phenylephrine infusion) and baroreceptor deactivation (nitroprusside infusion). These measurements were performed at baseline and after 4 weeks of exercise training. MEASUREMENTS AND RESULTS: Peak oxygen uptake increased significantly (12.3 +/- 10.7% [mean +/- SD]) with exercise training. Resting MSNA reduced from 34 +/- 12 to 27 +/- 8 bursts/min in the trained group but not in the untrained group. Arterial baroreflex sensitivity (BRS) [from 8.9 +/- 3.0 to 10.3 +/- 3.0 ms/mm Hg, p < 0.05] and MSNA response to baroreceptor stimulation (change of integrated MSNA from - 47 +/- 23 to - 70 +/- 21%, p < 0.01) improved significantly in the trained group, but not in the untrained group. Despite baroreceptor deactivation improving MSNA response in both groups, there was no significant difference between the two groups. CONCLUSIONS: Exercise training increased arterial BRS and decreased sympathetic nerve traffic after AMI, which indicate that the sympathoinhibitory effect of exercise training may, at least in part, contribute to the beneficial effect of exercise training in patients with AMI.

• Macrophage colony-stimulating factor (M-CSF), as well as granulocyte colony-stimulating factor (G-CSF), accelerates neovascularization.

  Authors: Keizo Minamino, Yasushi Adachi, Mitsuhiko Okigaki, Hidefumi Ito, Yoshimi Togawa, Kengo Fujita, Minoru Tomita, Yasuhiro Suzuki, Yuming Zhang, Masayoshi Iwasaki, Keiji Nakano, Yasushi Koike, Hiroaki Matsubara, Toshiji Iwasaka, Miyo Matsumura, Susumu Ikehara

  Stem cells (Dayton, Ohio). 04/2005; 23(3):347-54.

  It has been reported that bone marrow cells (BMCs) differentiate into endothelial cells of blood vessels, and that granulocyte colony-stimulating factor (G-CSF) mobilizes progenitors in the BMCs toIt has been reported that bone marrow cells (BMCs) differentiate into endothelial cells of blood vessels, and that granulocyte colony-stimulating factor (G-CSF) mobilizes progenitors in the BMCs to the peripheral blood, while macrophage colony-stimulating factor (M-CSF) augments the production of monocytes. We examined whether M-CSF augments the differentiation of BMCs into endothelial cells of blood vessels using a hindlimb-ischemic model. Either G-CSF or M-CSF, or both, was administered to the hindlimb-ischemic mice for 3 days. Both M-CSF and G-CSF augmented the differentiation of BMCs into endothelial cells of blood vessels through vascular endothelial cell growth factor (VEGF), resulting in early recovery of blood flow in the ischemic limbs.