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Biomedical subjects

Hideya Takenaka

Publications and source records attributed to Hideya Takenaka.

16 recordsLinked to original sources
PubMed2006

Topical sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling.

BACKGROUND: Sonic hedgehog (Shh) is a prototypical morphogen known to regulate epithelial-mesenchymal interaction during embryonic development. Recent observations indicate that exogenous administration of Shh can induce angiogenesis and may accelerate repair of ischemic myocardium and skeletal muscle. Because angiogenesis plays a pivotal role in wound repair, we hypothesized that activation of the hedgehog pathway may promote a favorable effect on microvascular remodeling during cutaneous wound healing and thereby accelerate wound closure. Because diabetes is associated with impaired wound healing, we tested this hypothesis in a diabetic model of cutaneous wound repair. METHODS AND RESULTS: In Ptc1-LacZ mice, cutaneous injury resulted in LacZ expression, indicating that expression of the Shh receptor Patched was induced and therefore that the Shh signaling pathway was intact postnatally and upregulated in the process of wound repair. In diabetic mice, topical gene therapy with the use of naked DNA encoding for Shh resulted in significant local gene expression and acceleration of wound recovery. The acceleration in wound healing was notable for increased wound vascularity. In bone marrow transplantation models, the enhanced vascularity of the wound was shown to be mediated, at least in part, by enhanced recruitment of bone marrow-derived endothelial progenitor cells. In vitro, Shh promoted production of angiogenic cytokines from fibroblasts as well as proliferation of dermal fibroblasts. Furthermore, Shh directly promoted endothelial progenitor cell proliferation, migration, adhesion, and tube formation. CONCLUSIONS: These findings suggest that a simple strategy of topically applied Shh gene therapy may have significant therapeutic potential for enhanced wound healing in patients with impaired microcirculation such as occurs in diabetes.

Angiogenic Proteins↗
PubMed2006

Endothelial progenitor thrombospondin-1 mediates diabetes-induced delay in reendothelialization following arterial injury.

Delayed reendothelialization contributes to restenosis after angioplasty and stenting in diabetes. Prior data have shown that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to endothelial recovery after arterial injury. We investigated the hypothesis that the EPC contribution to reendothelialization may be impaired in diabetes, resulting in delayed reendothelialization. Reendothelialization was significantly reduced in diabetic mice compared with nondiabetic mice in a wire-induced carotid denudation model. The EPC contribution to neoendothelium was significantly reduced in Tie2/LacZ BM-transplanted diabetic versus nondiabetic mice. BM from diabetic and nondiabetic mice was transplanted into nondiabetic mice, revealing that reendothelialization was impaired in the recipients of diabetic BM. To examine the relative roles of denuded artery versus EPCs in diabetes, we injected diabetic and nondiabetic EPCs intravenously after arterial injury in diabetic and nondiabetic mice. Diabetic EPCs recruitment to the neoendothelium was significantly reduced, regardless of the diabetic status of the recipient mice. In vitro, diabetic EPCs exhibited decreased migration and adhesion activities. Vascular endothelial growth factor and endothelial NO synthase expressions were also significantly reduced in diabetic EPCs. Notably, thrombospondin-1 mRNA expression was significantly upregulated in diabetic EPCs, associating with the decreased EPC adhesion activity in vitro and in vivo. Reendothelialization is impaired by malfunctioning EPCs in diabetes. Diabetic EPCs have phenotypic differences involving thrombospondin-1 expression compared with nondiabetic EPCs, revealing potential novel mechanistic insights and therapeutic targets to improve reendothelialization and reduce restenosis in diabetes.

Animals↗
PubMed2006

Cutaneous tissue angiotensin-converting enzyme may participate in pathologic scar formation in human skin.

BACKGROUND: Many studies have shown that up-regulation of angiotensin-converting enzyme (ACE) participates in adverse fibrous remodeling. Although this has become an accepted fact in the cardiovascular field, the relationship between ACE and cutaneous fibrous remodeling, such as keloid or hypertrophic scars, remains unknown. OBJECTIVE: We sought to investigate ACE in normal skin, wounded skin, and pathologic scars. METHODS: Ten samples undergoing a normal wound-healing process, 14 samples of pathologic scar tissue, and 15 samples of normal skin were used in this study. Cutaneous tissue ACE activities were measured with high-pressure liquid chromatography. Localization of ACE was assessed by immunohistochemistry. RESULTS: The ACE activity in pathologic scar tissue was significantly higher than in normal and wounded skin. Immunohistochemical studies demonstrated that myofibroblasts were stained with anti-ACE antibody. LIMITATIONS: The study is small. CONCLUSIONS: These results suggest that up-regulated ACE may participate in cutaneous pathologic scar formation the same as the cardiovascular system.

Adolescent↗
PubMed2006

Dibutyryl cAMP influences endothelial progenitor cell recruitment during wound neovascularization.

Delayed wound healing is one of the major complications of diabetes, and is caused by delayed cellular infiltration, reduced angiogenesis, and decreased formation and organization of collagen fibers. Recently, endothelial progenitor cells (EPC) isolated from peripheral blood were shown to accumulate at sites of neovascularization during wound healing. The present study tested the hypothesis that sodium N-6,2'-O-dibutyryl adenosine-3',5'-cyclic phosphate (DBcAMP), which has been shown to accelerate wound healing, promotes recruitment of EPC into wounds and contributes to the stimulation of neovascularization in genetically diabetic mice. Topical application of DBcAMP resulted in significant acceleration of wound healing and wound vascularization partly via enhanced recruitment of EPC. EPC in DBcAMP-treated wounds were mainly localized to cell clusters at the border of the granulation tissue, a site where blood supply is most insufficient. DBcAMP treatment increased the mRNA expression of angiogenic cytokines vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1alpha (SDF-1alpha) in vivo in wound tissue and in cultured fibroblasts and macrophages, in vitro. Culture supernatants of DBcAMP-treated cells enhanced EPC migration. Taken together, these results indicate that DBcAMP promotes neovascularization in wound healing, at least partly by increasing the accumulation of EPC at wound sites.

Animals↗
PubMed2006

Successful treatment of diabetic gangrene with topical application of a mixture of peripheral blood mononuclear cells and basic fibroblast growth factor.

Diabetic gangrene is a non-healing skin ulcer that is often resistant to most common treatments. It is caused by microvascular disorders and an immunocompromised state which are induced by diabetes mellitus. We report a 65-year-old man with an aggressive, refractory diabetic gangrene on his left foot. Treatment of his diabetic gangrene with topical application of a mixture of peripheral blood mononuclear cells (PBMC) and basic fibroblast growth factor (bFGF) resulted in a dramatic improvement in a short time. The ulcer was completely closed and, in the past 6 months, no new ulceration has been observed. The patient is able to stand and walk by himself. Topical application of a mixture of PBMC and bFGF appears to be a useful, non-invasive and convenient method for the treatment of diabetic gangrene.

Administration, Cutaneous↗
PubMed2006

Vaccination of Japanese patients with advanced melanoma with peptide, tumor lysate or both peptide and tumor lysate-pulsed mature, monocyte-derived dendritic cells.

We performed a clinical trial to assess the feasibility and efficacy of immunotherapy with peptides, tumor lysate or both peptides and tumor lysate-pulsed mature, monocyte-derived dendritic cells (DC) for advanced malignant melanoma patients that are resistant to conventional therapies. Sixteen patients were enrolled in this trial. All patients received DC vaccines i.d. in the proximal thigh, close to the inguinal lymph nodes, one treatment per week or 2 weeks. Several factors such as clinical findings, computed tomography (CT) images, delayed type hypersensitivity (DTH) response, enzyme-linked immunosorbent spot (ELISPOT) assay, and immunohistochemistry in primary, metastatic lesions and the DTH site were evaluated. Clinical results through DC vaccination were as follows: in 11 evaluable cases, three stable disease, six progression of disease and two disease-free from the time of study entry to the completion of one vaccination course. One patient showed reduction of the tumors in the metastases on chest CT during the first and second course of DC vaccination. Ten out of 14 evaluable cases showed positive DTH responses to more than one treatment with melanoma peptides or tumor lysate. Eight out of 13 evaluable cases showed positive immunological responses to more than one treatment with melanoma peptides or tumor lysate in an ELISPOT assay. As for the experiences with toxicity and adverse reactions, autosensitization dermatitis-like eruptions appeared in five cases during DC vaccination. No severe adverse effects were seen in any of the patients. In our study, the clinical efficacy in prolongation of the patients' survival was confirmed. At the same time, cancer immunoediting of the tumor was also found. It will be necessary to improve the tumor-specificity of this therapeutic approach and to analyze the mechanism(s) of tumor escape from immunosurveillance in melanoma.

Adult↗
PubMed2005

Sonic hedgehog myocardial gene therapy: tissue repair through transient reconstitution of embryonic signaling.

Sonic hedgehog (Shh) is a crucial regulator of organ development during embryogenesis. We investigated whether intramyocardial gene transfer of naked DNA encoding human Shh (phShh) could promote a favorable effect on recovery from acute and chronic myocardial ischemia in adult animals, not only by promoting neovascularization, but by broader effects, consistent with the role of this morphogen in embryogenesis. After Shh gene transfer, the hedgehog pathway was upregulated in mammalian fibroblasts and cardiomyocytes. This resulted in preservation of left ventricular function in both acute and chronic myocardial ischemia by enhanced neovascularization, and reduced fibrosis and cardiac apoptosis. Shh gene transfer also enhanced the contribution of bone marrow-derived endothelial progenitor cells to myocardial neovascularization. These data suggest that Shh gene therapy may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by triggering expression of multiple trophic factors and engendering tissue repair in the adult heart.

Acute Disease↗
PubMed2005

Atypical fibroxanthoma on a bald scalp.

We present the clinical, histopathological and immunohistochemical findings of an atypical fibroxanthoma (AFX) on the bald scalp of an 81-year-old French man who had worked at a private high school in Japan as a janitor for over 40 years. The patient had a history of basal cell carcinoma on the nape, and chronic solar radiation seemed to be a predisposing factor in the pathogenesis of this association. This case showed the typical clinical and histopathological characteristics of AFX, and the immunohistochemical results suggested differentiation of histiocytes and myofibroblasts. The AFX was completely resected, and the patient has not had tumor recurrence or metastasis for over four postoperative years. This case therefore provides further support to the theory that AFX displays a clinically benign course, even though it is essentially a malignant tumor histologically located in the dermis. Therefore, we must excise AFX completely with great care and perform regular physical examinations for several years after operation.

Aged, 80 and over↗
PubMed2005

Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages.

In the inflamed cornea, there is a parallel outgrowth of blood and lymphatic vessels into the normally avascular cornea. We tested whether adaptive and/or innate immune cells were actively involved in the genesis of new lymphatic vessels. Our results indicate that innate immune cells (CD11b+ macrophages, but not CD11c+ dendritic cells) physically contributed to lymphangiogenesis under pathological conditions and that bone marrow-derived CD11b+ macrophages expressed lymphatic endothelial markers such as LYVE-1 and Prox-1 under inflamed conditions in the corneal stromata of mice. Furthermore, blood vascular endothelial cells that expressed the Tie2 promoter did not contribute to newly formed lymphatic vessels under inflamed conditions. Our in vitro experiments demonstrated that CD11b+ macrophages alone were capable of forming tube-like structures that expressed markers of lymphatic endothelium such as LYVE-1 and podoplanin. The novel finding that CD11b+ macrophages are critical for the development of inflammation-dependent lymphangiogenesis in the eye suggests a new mechanism of lymphangiogenesis.

Animals↗
PubMed2003

Localized cutis marmorata telangiectatica congenita on the back of a young man.

We report the clinical and light microscopic features of a case of cutis marmorata telangiectatica congenita with a painful refractory ulcer that was found on the back of a young Japanese man. The ulcer was positioned on the upper back over the spinal bone. In addition to the anatomical location of the ulcer, the vascular ectases may have played a part in the refractory ulceration.

Adult↗
PubMed2002

Immunolocalization of fibroblast growth factor receptors in normal and wounded human skin.

Fibroblast growth factors (FGFs) have been shown to play diverse roles in various tissues. To define their sites of action in normal human skin and during wound healing, we determined the protein expression of the four known fibroblast growth factor receptors (FGFRs) in normal and wounded human skin by immunohistochemistry. Four receptors (FGFR-1 to FGFR-4) showed distinct patterns of expression in normal skin. Expression of FGFR-1 was widespread in the epidermis, appendages, arrector pili muscles, blood vessels, and dermal fibroblasts. Intense expression of FGFR-2 and FGFR-4 was seen in the arrector pili muscles and smooth muscle cells of vessels. In the epidermis, the basal layer showed immunoreactivity for FGFR-2, whereas the suprabasal layers and the inner layers of hair follicles showed strong immunoreactivity for FGFR-3. In wounded skin, there was strong expression of FGFR-1 and FGFR-3, and moderate expression of FGFR-2 and FGFR-4 in the basal layer in newly forming epidermis. In granulation tissues, neocapillaries expressed all four FGFRs, fibroblasts/myofibroblasts expressed FGFR-1 and FGFR-3, and mononuclear inflammatory cells expressed FGFR-1 and FGFR-3. Our results suggest that the differences in the spatial patterns of FGFR expression in normal skin may generate functional diversity in response to FGFs and that in wounded skin, FGFs may function in wound healing via the induced FGFRs.

Burns↗