We have previously shown that embryonic stem (ES)-like cells can be induced from mouse fibroblasts, hepatocytes and stomach epithelial cells by introducing four factors (Oct3/4, Sox2, c-Myc, and Klf4). The cells are similar in morphology, proliferation and gene expression profile to those of ES cells, and are called induced pluripotent stem (iPS) cells. When the iPS cells are transferred into blastocyst, they can contribute to adult chimeric mice and transmit through germline to the next generation. Therefore iPS cells have almost same differentiation potential as ES cells. In 2007, we and others reported the establishment of iPS cells from human somatic cells and showed their pluripotency.
These iPS cells would supply patient-specific pluripotent stem cells for cell transplantation therapies. However, iPS cells still have several problems to be overcome, especially tumorigenicity owing to the use of oncogenes and retrovirus. Recent studies revealed that c-Myc is not a crucial factor for iPS induction, albeit it greatly increases the efficiency. The improvement of reprogramming efficiency was reported with soluble factor, Wnt3a, and several small molecules that influence epigenetic modification, such as BIX-01294 and VPA. Induction of mouse iPS cells without virus vector has been reported. Through the basic researches on iPS and ES cells, molecular mechanisms underlying the reprogramming process were gradually being uncovered. Here we try to summarize current studies on iPS cells. The iPS cells will contribute to the fields ofelucidation of pathogenesis, drug discovery, toxicology study, and cell transplantation therapy in the future.

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Nuclear factor-κB (NF-κB) plays an essential role in optimal activation of host immune systems, which isconserved from insects to mammals. Various microbial components and host-derived inflammatory cytokines activate NF-κB, leading to activation of the host immune system. Since excessive activation of NF-κB is harmful to the host, its activity is finely regulated at multiple steps in immune signaling pathways. One mechanism to prevent NF-κB activation is conducted by cytoplasmic IκB family proteins. Cytoplasmic IκBs have been shown to interact with NF-κB subunits in the cytoplasm of unstimulated cells. On stimulation, IκBs are rapidly degraded in a ubiquitin-proteasome dependent manner, allowing liberated NF-κB to translocate into the nucleus and activate the transcription of genes encoding various immune mediators. After the translocation of NF-κB from the cytoplasm to the nucleus, nuclear proteins structurally similar to cytoplasmic IκBs participate in the regulation of NF-κB activity as co-activators or -inhibitors through association with NF-κB subunits. For that reason, the regulatory IκB-like nuclear molecules are known as ‘nuclear IκB proteins’. In this review, we will discuss the physiological function of the nuclear IκB proteins, IκBξ, IκBNS, and Bcl-3 in the context of innate and adaptive immune responses.

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In retinal detachment and in several other visual disorders, photoreceptor apoptosis represents the major cause of vision loss. The mechanisms underlying photoreceptor apoptosis, however, remain elusive. Here, we review our recent publications on the pathogenesis of retinal detachment-induced photoreceptor apoptosis and discuss the critical role of monocyte chemoattractant protein-1 (MCP-1) in mediating photoreceptor apoptosis in an experimental rodent model of retinal detachment. Elevated levels of MCP-1 are found in vitreous samples from patients with retinal detachment. MCP-1 expression is similarly increased in our rodent model after retinal detachment, with MCP-1 expression being detected in Muller glia. Moreover, CD11b-immunopositive macrophages/microglia are recruited into the detached retina. Interestingly, the suppression of MCP-1 with an MCP-1—blocking antibody or through MCP-1 gene deletion, as in MCP-1—deficient mice, significantly reduces macrophage/microglia infiltration and photoreceptor apoptosis. To investigate whether MCP-1 contributes to photoreceptor apoptosis by directly affecting photoreceptors or by indirectly affecting photoreceptors through recruited macrophages/microglia, we examined the effect of MCP-1 on primary retinal mixed cultures and the induction of retinal detachment in Mac-1 (CD11b/CD18)-deficient mice. Our data showed that MCP-1 cytotoxicity toward cultured photoreceptors occurs through resident microglia. Moreover, eliminating macrophage/microglia infiltration in vivo decreases photoreceptor apoptosis after retinal detachment. Thus, retinal detachment induces increased expression of MCP-1 in Müller cells and increased infiltration and activation of macrophages/microglia, resulting in photoreceptor apoptosis. This pathway may be an important therapeutic target for preventing photoreceptor apoptosis in retinal detachment and other central nervous system diseases that share a common etiology.

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Uncontrolled fibrosis due to the excessive accumulation of extracellular matrix proteins plays a primary role in the lacrimal gland dysfunction of patients with ocular chronic graft-versus-host disease (GVHD). To investigate the pathogenesis of this disease, lacrimal gland biopsies obtained from patients with chronic GVHD were analyzed and compared with those from Sjögren's syndrome (SS) patients, as controls. Increased numbers of CD34⁺ fibroblasts and excessive fibrosis in the affected area was prominent, indicating a significant role for stromal fibroblasts in ocular chronic GVHD. The periductal area was the primary site for T-cell and fibroblast activation. A subset of fibroblasts that had accumulated in the affected area expressed HLA-class II and costimulatory molecules; such fibroblasts were not observed in SS lacrimal glands. In addition, donor fibroblast chimerism, which may also contribute to the pathogenic processes of this disease, were detected in the pathogenic fibrotic area. Moreover, T cells interacted with the lacrimal gland myoepithelia, which become HSP47-expressing cells under inflammatory stress. This mini-review will focus on recent researches on the immune response and pathogenic fibrosis in human ocular chronic GVHD, in which we examined the lacrimal gland as one of the targeted exocrine glands. These findings may help elucidate the pathogenesis of lacrimal gland as well as systemic chronic GVHD fibrosis and facilitate the development of novel anti-fibrotic interventions.

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There is an increasing body of evidence that suggests that malignant tumors, such as leukemia, breast cancers, and brain cancers, contain cells that maintain the characteristics of tissue-specific stem cells (TSSCs) and are malignant. Malignant gliomas, for example, contain proliferating cells expressing neural stem cell (NSC) markers, such as nestin and CD133, and differentiating cells expressing either neuronal markers or glial markers, raising the possibility that the tumors may contain NSC-like cancer cells. Additional evidence also exists, which indicate that malignant tumors might contain stem cell-like cancer cells, called “cancer stem cells” (CSCs) or “tumor initiating cells”. Although a number of anti-cancer drugs and irradiation therapy have been successful in eliminating cancers, occasionally some cancer cells survive and invade other tissues, leading to the recurrence of cancer; this indicates that the surviving cells are not only resistant to such anti-cancer drugs and irradiation but are also malignant. Previous studies have shown that various ATP binding cassette transporters, such as the multi-drug resistant protein encoded by the multi-drug resistant gene, and the breast cancer resistant protein 1 (BCRP1), contribute to drug resistance in cancers. Interestingly, some of these transporters are also expressed in many types of normal stem cells. BCRP1, for example, excludes the fluorescent dye Hoechst 33342, identifying a side population (SP) enriched with TSSCs. Taking advantage of the common characteristics that exist between TSSCs and cancer cells, many groups have demonstrated that CSCs in tumors or cancer cell lines can self-renew, express well-known TSSC markers, form tumors when transplanted in vivo and show resistance to anti-cancer treatments; this suggests that CSCs are important targets for curable therapy. In order to develop an effective therapy against tumors, characterizing and finding ways to kill CSCs is essential. In this review, I have summarized the recent progresses made in glioma CSC research and discuss the perspectives of this field.

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Aims: Renal artery stenosis (RAS) and aortic aneurysm are becoming more common growing because of the increased mean age of the population and the greater prevalence of hypertensive and diabetic patients. Here we report on the clinical course of abdominal aortic aneurysm (AAA) associated with RAS, and analyze the laboratory data and pathological findings.
Patients and Methods: Thirty-eight operated patients and two treated conservatively were divided into twogroups, i.e., 10 patients with RAS and 30 without RAS. Then we observed the prognosis of five young patientswith renal artery fibromuscular dysplasia without AAA to clarify that of systemic atherosclerotic patients.
Results: Renal function had already declined before admission and rapidly decreased further after surgery in 7 of the 10 patients with RAS and their prognosis was very poor, particularly in the case of 3 patients with cholesterol crystal embolism. Two RAS patients suffered rupture of aneurysm while waiting for surgery on hemodialysis. Advanced ischemic changes were observed in the kidneys of RAS patients. Two patients with unilateral renal artery stenosis showed severe histologic changes of both kidneys.
Conclusion: The pathogenesis and symptoms of RAS with AAA are complex, and it is important to select adequate treatment for each patient, considering the systemic status carefully.

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