Hematopoietic stem cells (HSCs) give rise to variety of hematopoietic cells, and are responsible for blood production throughout adult life. Recent studies have demonstrated the potential of HSCs to produce various nonhematopoietic cells. Amplification of HSCs represents a potentially powerful approach not only to the treatment of various blood disorders but also to applying gene therapy or to regenerative medicine. Lnk is an adaptor protein consisting of PH, SH2 domains, and a C-terminal tyrosine phosphorylation site. Marked expansion of Blineage cells occurs in lnk^-/- mice, indicating Lnk regulates B cell production by negatively controlling growth signals through c-Kit in B cell precursors. Lnk is also expressed in hematopoietic progenitors, and the number and the hematopoietic ability of HSCs are significantly increased in the absence of Lnk. While augmented signaling through c-Kit partly contributed to the increased progenitor cells in lnk^-/- mice, it is likely that there exist Lnkdependent but c-Kit-independent signaling pathways whose absence leads to augmented ability of lnk^-/- HSCs. These indicate that Lnk plays critical roles in the expansion and function of HSCs and provide useful clues for the amplification of HSCs and progenitor cells.

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In bone marrow, stromal cells may provide the microenvironment for self-renewal and differentiation of hematopoieticstem/progenitor cells through complex cell-cell interaction. To elucidate the regulatory mechanisms ofhematopoiesis by stromal cells, we established many stromal cell lines from various hematopoietic organs. Wethen reconstructed the in vitro hematopoietic microenvironment and succeeded to establish the stroma-dependenthematopoietic cell lines. This in vitro system may be useful to find regulatory factors involved in the hematopoietic microenvironment.

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Allergic diseases are complex disorders involving a combination of genetic and environmental factors. In case of bronchial asthma, these factors result in infiltration of Th-2 lymphocytes, mast cells and eosinophils into asthmatic airways with downstream mediator release and disordered airway function. Cytokines derived from the Th-2 lymphocytes are considered to orchestrate the asthmatic phenotype. Among Th2 cytokines, the significance of IL-13 in the pathogenesis of bronchial asthma has recently emerged. Particularly, the direct action of IL-13 on bronchial epithelial cells is critical for generation of airway hyperresponsiveness. IL-13 signal is regulated by two receptors; one is the heterodimer composed of the IL-13 receptor α1 chain and the IL-4 receptor α chain which transduces IL-13 signal, and the other is the IL-13 receptor α2 chain which blocks the IL-13 signal. In this review article, we present our recent findings about the expression mechanism of the IL-13 receptors on bronchial epithelial cells and the functional role of a single nucleotide polymorphism on IL13 gene as a genetic factor. These findings give us a hint to improve the asthmatic condition by blocking the IL-13 actions.

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Developing skull sutures are the place in which osteogenic cell proliferation-differentiation balance is maintained. Mutations in fibroblast growth factor receptors (FGFRs) and TWIST cause congenital anomaly called craniosynostosis defined as early closure of one or more cranial sutures. Previous studies have suggested: 1) TWIST is expressed in the sutural mesenchyme maintaining undifferentiated condition; 2) FGFR2 expression is associated with proliferation of osteogenic progenitor cells; 3) FGFR1 expression regulates osteoblast differentiation. In order to evaluate this hypothesis we carried out immunohistochemical detection of cell cycle regulators in mouse developing suture. Cell cycle regulators which promote cell proliferation are mainly present where Fgfr2 is expressed, they are also detected in some of the sutural cells. Other cell cycle regulators that inhibit cell cycle progression localize in cells adjacent to the osteoid in which Fgfr1 is expresssed. These results support the hypothesis and suggest that mutations in the genes induce the imbalanced osteogenic differentiation resulting in early suture fusion.

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Periodontal ligament (PDL) is a thin non-mineralized connective tissue between two mineralized tissues: alveolar bone and cementum. PDL keeps its function under enormous mechanical stress. In this article, I will introduce our studies characterizing the uniqueness of PDL and then discuss regeneration of periodontal tissue. S100A4 is a small Ca binding protein and we found high expression level of S100A4 in PDL. Histologically S100A4 localized on extracellular matrix and analysis of culture medium of PDL fibroblasts revealed secretion of S100A4 and recombinant S100A4 protein inhibited mineralization of osteoblastic culture. MC3T3-E1 cells (mouse osteoblastic cell line) expressed S100A4 at very low level and inhibition of S100A4 with a retroviral vector containing S100A4 antisense enhanced the mineralization of MC3T3-E1 cell culture. Finally, when PDL cells were exposed under mechanical stress in culture, expression level of S100A4 increased. These results indicate that S100A4 acts as a mineralization inhibitor in PDL and also bone; and that this protein plays a role in keeping its function under enormous mechanical stress. Although PDL is a non-mineralized tissue, it contains progenitors of osteoblasts and cementoblasts. Indeed, PDL is prerequisite for periodontal tissue regeneration. Application of guided tissue regeneration (GTR) and/or enamel matrix derivative (EMDOGAIN) promote periodontal tissue regeneration. Treatment with a dental implant, which is inserted to edentulous bone, is clinically acceptptable; however, a dental implant with PDL like a natural tooth would be more ideal.

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It has long been recognized that the microvasculature is exquisitely sensitive to ischemia/reperfusion (I/R) and that hyperadhesiveness of leukocytes to endothelial cells contributes to I/R-induced tissue injury. The phenomenon of I/R has been implicated in the microvascular and parenchymal cell injury associated with several pathological conditions, including gastric ulcer formation, multiple organ failure, cancer metastasis, and organ transplantation. In an effort to define the mechanisms responsible for reperfusion-induced vascular injury, a number of in vitro models have been developed to simulate the responses of endothelial cells to I/R. Due to its simplicity, many investigators have employed monolayers of cultured endothelial cells exposed to anoxia, followed by reoxygenation (A/R) as a model system to mimic I/R-induced vascular changes in vivo.
This review will provide an overview of our current understanding of leukocyte-endothelial cell interactions derived from in vitro studies of endothelial cell monolayers exposed to anoxia/reoxygenation, with specific emphasis on the molecular determinants mediating this inflammatory process and the contribution of reoxygenationinduced oxidative stress to the activation of NF-kB and the expression of endothelial surface adhesion molecules.

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Exuberant accumulation of smooth muscle cells plays a principal role in the pathogenesis of vascular diseases. It has been assumed that smooth muscle cells derived from the adjacent medial layer migrate, proliferate and synthesize extracellular matrix. Although a lot of effort has been devoted targeting migration and proliferation of medial smooth muscle cells, no effective therapy to prevent occlusive vascular remodeling has been established. Here, we show that bone marrow cells give rise to the majority of smooth muscle cells that contribute to arterial remodeling in models of post-angioplasty restenosis, graft vasculopathy and hyperlipidemia-induced atherosclerosis. Notably, purified hematopoietic stem cells differentiated into smooth muscle cells in vitro and in vivo. Our findings suggest that somatic stem cells contribute to pathological remodeling of remote organs. Our study provides the basis for the development of a new therapeutic strategies for vascular diseases, targeting mobilization, homing, differentiation and proliferation of bone marrow-derived vascular progenitor cells.

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We report here a 47-year-old female who had episode of acute pancreatitis three times after banana ingestion. After each admission clinical symptoms such as epigastric pain, nausea, vomiting and diarrhea were disappeared within a few days with a light diet and intravenous fluids in parallel with normalizing serum amylase levels. Serum total IgE level was elevated and serum specific IgE level to banana was 2.18 UA/ml. No remarkable abnormalities were present in sonography, computed tomography (CT), magnetic resonance image (MRI) on the abdomen, and magnetic resonance cholangiopancreatography (MRCP). Endoscopic examination of the upper digestive tract, showed that the ampulla of Vater was swollen and edematous. Toluidine blue staining and immunohistochemical staining against human mast cell tryptase with biopsy specimens showed mast cells accumulation in mucosa and submucosa of the stomach. Even though the provocation test by banana could not be performed, the patient was diagnosed as having pancreatitis possibly caused by allergy to banana because she has not suffered any attacks of pancreatitis since the third attack by avoiding ingestion of banana.

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