The intestinal epithelium constitutes a physical barrier between inner and outer side of our body. It also functions as a "hub" which connects factors that determine the development of inflammatory bowel disease, such as microbiota, susceptibility genes, and host immune response. Accordingly, recent studies have implicated and further featured the role of intestinal epithelial cell dysfunction in the pathophysiology of inflammatory bowel disease. For example, mucin producing goblet cells are usually "depleted" in ulcerative colitis patients. Studies have shown that those goblet cells exhibit various immune-regulatory functions in addition to mucin production, such as antigen presentation or cytokine production. Paneth cells are another key cell lineage that has been deeply implicated in the pathophysiology of Crohn's disease. Several susceptibility genes for Crohn's disease may lead to impairment of anti-bacterial peptide production and secretion by Paneth cells. Also, other susceptibility genes may determine the survival of Paneth cells, which leads to reduced Paneth cell function in the patient small intestinal mucosa. Further studies may reveal other unexpected roles of the intestinal epithelium in the pathophysiology of inflammatory bowel disease, and may help to develop alternative therapies targeted to intestinal epithelial cell functions.

Genetically modified T-cells with forced expression of anti-CD19 chimeric antigen receptor (CD19 CAR) have demonstrated promising clinical results for relapsed and refractory B cell malignancies in early clinical trial settings. The first beneficial tumor regressions were identified among approximately half of CLL patients in 2011. Similarly, CD19 CAR T-cells achieved remissions in about 80% of aggressive B-cell lymphomas in 2012. Furthermore, in 2013 this cellular therapy showed an extremely high rate of efficacy against refractory CD19 positive acute lymphoid leukemia, which had been regarded as the most difficult to treat hematologic disease. Recently, despite the absence of CD19 expression by neoplastic plasma cells, patients with refractory multiple myeloma achieved stringent complete remission after this therapy coupled with high dose chemotherapy and autologous stem cell transplantation. However, there are significant toxicities. Cytokine releasing syndrome and neurotoxicity are recognized as life-threatening adverse events. Although phase I/II clinical trials have just started in Japan, given the exciting results obtained to date, this cellular therapy is expected to be a novel breakthrough immunotherapy for treating refractory B-cell malignancies.

A 60-year-old man with myelodysplastic syndrome underwent allogeneic transplantation of female umbilical cord blood in 2010 and sustained a complete remission. He experienced severe pain in his left hip joint and was admitted to the orthopedic surgery division of our institution in February 2015. After admission, he was suspected to have hemophagocytic syndrome (HPS) and was thus transferred to the hematology division. Bone marrow aspiration revealed hyper-cellular marrow filled with abnormal collapsed cells, consistent with bone marrow necrosis (BMN). As there was no evidence of infection, collagen disease, or occult cancer, he was diagnosed with HPS of unknown origin and treated with dexamethasone, cyclosporine A, and etoposide according to the HLH-2004 protocol. Although his general condition and laboratory findings showed amelioration, morphologically abnormal cells appeared in peripheral blood two weeks after treatment. Bone marrow aspiration showed BMN with increased abnormal cells, positive for CD117 and MPO. Sex chromosome FISH analysis revealed donor chimerism and cytogenetic analysis showed 46XX, +1, der (1;7) (q10;q10). He was diagnosed with donor cell leukemia (DCL) and received salvage chemotherapy. However, he died because of severe pneumonia and sepsis without neutrophil recovery at day 68. We herein report this rare case of DCL with BMN.

A 58-year-old man was diagnosed with accelerated phase chronic myelogenous leukemia (CML). He was treated with dasatinib and followed-up; 6 months later, he achieved a complete molecular response. Seventeen months after this therapy, he developed pancytopenia, and was examined. His diagnosis was Ph-negative acute myeloid leukemia (AML) with no karyotype abnormalities. He was administered two courses of induction chemotherapy, and during the first remission, he received allogeneic hematopoietic stem cell transplantation. Treatment with a tyrosine kinase inhibitor (TKI) achieved a successful outcome. However, approximately 10% of CML cases develop clonal cytogenetic changes in Ph-negative cells during TKI treatment, and rarely, cases of Ph-negative myelodysplastic syndrome or AML are reported. Furthermore, similar to our case, CML patients developing AML with Ph-negative and normal chromosome abnormalities have been reported. We suggest vigilant monitoring during TKI therapy and stress the importance of further analysis based on similar accumulated cases.

Leukemia is derived from hematopoietic stem/progenitor cells that have acquired genetic abnormalities, leading to malignant transformation. The basis of therapyfor leukemia is a combination of anti-cancer drugs based on risk stratification. The overall 5-year survival rate in leukemia patients of all ages is still 40%, although it has improved in pediatric patients. Leuke- mia itself is a heterogeneous disease that includes various entities/subtypes with different pathogenic gene aberrations. Selection of the treatment strategylargelydepends on risk stratification, and this in turn is mainlybased on specific recurrent chromosome aberrations. However, in acute myeloid leukemia(AML), a significant proportion of patients present with a normal karyotype according to conventional cytogenetic analysis and are classified into an intermediate-risk group, which actuallyconsists of various subtypes with different prognoses. In addition, leukemic cells usuallyharbor one or more driver mutations among their various genetic aberrations, and these driver mutations could affect prognosis. The discoveryof additional mutations in genes such as NPM1, CEBPA and FLT3, which are frequent in AML patients with a normal karyotype, have improved the precision of risk stratification in AML. In this regard, array-based gene expression analysis and whole exome/ transcriptome sequencing could be useful tools for identifying the whole spectrum of genetic aberrations, or for compiling a complete list of mutated genes within leukemic cells. Genetic profiling information obtained using these newlydeveloped methods could provide more accurate information for molecular subtyping and risk stratification in leukemia.

Nowadays, antibiotic resistance is a serious global health concern, for it is observed every- where on the earth. While antibiotic is effective for controlling pathogens, an inappropriate use of the antibiotic leads to antibiotic resistance. Given that the ability to develop novel anti- biotics is quite limited, a new strategy must be developed to fight against it. Mucosal- associated invariant T cells (MAITs) belong to a family of the innate-like T cells that bridges the gap between the innate and the adaptive immunity. We have generated iPSCs from MAITs and redifferentiated MAITs from the iPSCs. These MAITs exerted anti- mycobacterial activity in mice. Advent of such cells will pave the way to exploit a novel arsen- al against antibiotic resistance.

Understanding regeneration of the trabecular structure in cancellous bone defects is an important issue in bone tissue engineering and regenerative medicine. Biochemical and biomechanical viewpoints are indispensable for understanding the fundamental mechanism that underlies the regeneration of the trabecular structure. In vitro observations of the Turing pattern-like bone differentiation into osteoblasts from human mesenchymal stem cells suggest that mathematical modeling and simulation based on a reaction-diffusion system model would help us to understand the mechanism of trabecular pattern formation during cancellous bone regeneration. In this article, we propose a mathematical model of trabecular morphogenesis based on the reaction-diffusion system in 3D, which comprises activators and inhibitors of bone formation by combining with mechanical factors. Based on the proposed model, we conduct computational simulation of trabecular regeneration in a cancellous bone defect using a voxel-based finite element method for stress analysis and a finite difference method for reaction-diffusion analysis. The proposed model could express the regeneration of the three-dimensional trabecular structure with mechanically adapted functions as a load-bearing structure. Based on these results, the proposed model and simulation framework are expected to facilitate the analysis of regeneration of the cancellous bone;this will help us to examine bone regeneration that involve complex biological factors.

Recently, control of mechanobiologic response of cells has been a strong attractive issue for biomaterials sciences in relation to the requirements for optimization of cell-materials interactions. In this mini-review, we survey the typical parameters for designing the biomaterials to manipulate cell mechanobiology, i.e., mechanobio-materials. In addition, from the view of regenerative biomedical engineering, we introduce our recent approaches on the development of mechanobio-materials for stem cell manipulation that ensures the high-qualified stemness.

Age-related macular degeneration is one of the leading causes of blindness characterized by progressive dysfunction of retinal pigment epithelium (RPE) and RPE transplantation. The replacement of pathological RPE with healthy RPE, is being investigated for AMD treatment. In recent years increasing attention has been given to human induced pluripotent stem cells (hiPSCs) as a useful cell source for RPE transplantation. We generated hiPSC-derived RPE (hiPSC-RPE) cell sheets optimized to meet clinical use requiring efficacy, consistency, and safety. These grafts consist of a monolayer of cells without any artificial scaffolds, and express typical RPE markers, form tight junctions that exhibit polarized secretion of growth factors, and show phagocytotic ability and gene expression patterns similar to those of native RPE. Additionally, autologous non-human primate iPSC-RPE cell sheets showed no immune rejection or tumor formation. These results suggest that autologous hiPSC-RPE cell sheets may serve as a useful cell source for RPE transplantation.

Once the Epstein-Barr virus (EBV) has infected a person, it then latently infects B cells. This latent infection lasts a lifetime. However, EBV can infect T or NK cells (T/NK cells) in rare cases. Therefore, EBV causes various hematological diseases. Among these diseases, CAEBV is regarded as the most problematic because, although it is not particularly uncommon, the diagnostic tests for this disease are not covered by health insurance, a serious illness in the "non-active" periods is lacking, and the appropriate motivation for early initiation of treatment can easily be lost. However, the symptoms may suddenly change; and if the manifestations are resistant when such exacerbation occurs, CAEBC is potentially lethal. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure. Once the diagnosis has been made, earlier treatment initiation, safer bridging to allogeneic HSCT with multi-drug chemotherapy, and then, planned HSCT can be completed more safely and thereby achieve a better outcome.

Adoptive immunotherapy using genetically modified T-cells is an emerging and promising treatment modality for various malignant diseases. The technology involves engineering of T-cells armed with well-characterized receptors such as T-cell receptors or chimeric antigen receptors. The latter is comprised of antibody/ligand and intracellular signaling domains. These molecules can be further modified to enhance their affinity, specificity, and several other functions. The success of adoptive immunotherapy is rooted in the application of extensive insights derived from allogeneic hematopoietic stem cell transplantations (HSCT). Herein, the historical perspectives of gene-modified T-cell therapy are discussed by comparison with the evolution of allogeneic HSCT. Furthermore, the prospects for the development and improvement of these powerful therapeutic methods are also highlighted.

Allogeneic hematopoietic stem cell transplantation (HSCT) has been applied for the treatment of inherited bone marrow failure syndromes, inherited metabolic diseases, and primary immunodeficiencies. HSCT indications for some inherited disorders are still controversial because the effects on neurocognitive function have been found to be variable, according to pre-transplant conditions including the patient's age, disease severity, disease status, and donor availability. Moreover, utmost attention must be paid to determining the preparative regimen for preventing regimen-related toxicity because the genetic effect was found to be expressed not only in the hematopoietic stem cells themselves but also in systemic tissues. Herein, recent progress and advances in the fields of HSCT for inherited diseases are reviewed.

Long survival is obtained in 30-40% of adult T-cell leukemia-lymphoma (ATL) patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT) using HLA-matched related or unrelated donors. Myeloablative conditioning is generally used for patients 55 years of age and older, while reduced intensity conditioning is given to those between 50-70 years of age. Overall survival periods do not differ significantly between these two conditioning methods. Survival rates with cord blood transplantation are not inferior to those obtained with bone marrow transplantation or peripheral blood stem cell transplantation. Prognostic factors such as age, gender, performance status, disease status at transplantation and serum soluble interleukin-2 receptor are known to have an impact in ATL patients receiving allo-HSCT. Mild acute graft-versus host disease is associated with good overall survival. Cessation of immunosuppressants or donor lymphocyte infusion often induces another remission in relapsed ATL patients after allo-HSCT. This phenomenon is regarded as a graft-versus-ATL effect mediated by activated cytotoxic T-cells. Donor cell derived-ATL has, on rare occasion, been reported in patients receiving allo-HSCT from HTLV-1 carrier donors. Special attention should be paid to the use of mogamulizumab before allo-HSCT, since this agent kills normal regulatory T-cells as well as ATL cells.

Methylprednisolone administered at a dose of 2 mg/kg is a standard first-line systemic therapy for grade II to IV acute graft-versus-host disease (GVHD). Lower dose methylprednisolone or prednisone, at doses of 0.5-1.0 mg/kg, is also accepted as a first-line therapy for mild acute GVHD. Response rates of grade II to IV acute GVHD to systemic corticosteroid therapy in Japanese patients range from 40-70%, depending on the donors. No improvement within 5 days after first-line therapy or progression within 3 days after first-line therapy could make patients eligible for second-line treatment. However, due to there being few treatment options for steroid-resistant acute GVHD, decisions to initiate second-line treatment are on occasion made 2-3 weeks after first-line therapy in Japan. Previous studies do not support the choice of any specific agent for second-line treatment of acute GVHD. Anti-thymocyte globulin and mesenchymal stem cells are covered by health insurance in Japan. Establishment of new evidence for GVHD treatment is required.

Myelodysplastic syndromes (MDS) are characterized by clonal proliferation of hematopoietic stem/progenitor cells and their apoptosis, and show a propensity to progress to acute myelogenous leukemia (AML). Although MDS are recognized as neoplastic diseases caused by genomic aberrations of hematopoietic cells, the details of the genetic abnormalities underlying disease development have not as yet been fully elucidated due to difficulties in analyzing chromosomal abnormalities. Recent advances in comprehensive analyses of disease genomes including whole-genome sequencing technologies have revealed the genomic abnormalities in MDS. Surprisingly, gene mutations were found in approximately 80-90% of cases with MDS, and the novel mutations discovered with these technologies included previously unknown, MDS-specific, mutations such as those of the genes in the RNA-splicing machinery. It is anticipated that these recent studies will shed new light on the pathophysiology of MDS due to genomic aberrations.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired GPI deficiency caused by somatic mutation of the PIGA gene in one or several hematopoietic stem cells. Recently, PNH caused by somatic mutation of one allele of the PIGT gene in combination with a germline mutation of the other allele was reported, showing that PIGA is not the only gene responsible for PNH, though other causes are rare. These mutant cells become GPI deficient, expand clonally and differentiate into all of the hematopoietic lineages. When GPI deficient erythrocytes increase in proportion, massive hemolysis occurs due to activated complement attack during infection. As the complement regulatory proteins such as CD59 and DAF are GPI anchored proteins, they are defective on GPI deficient erythrocytes and these abnormal erythrocytes are thereby left unprotected from complement attack. Hemolytic anemia, venous thrombosis, and bone marrow failure are thus the resulting triad of symptoms. Clonal expansion does not occur with PIGA deficiency alone. We hypothesize that PIGA deficient cells acquire a proliferative phenotype via additional gene mutations within the associated environment of bone marrow failure. This hypothesis will be explained by introducing recent reports.

The KEAP1-NRF2 system is an inducible molecular mechanism enhancing transcriptions of several cytoprotective genes in response to xenobiotics and oxidative stress. Recently, the KEAP1-NRF2 system has been suggested to directly regulate a portion of the genes related to cell proliferation and differentiation. In hematopoietic cells, NRF2 activation plays a role in maintenance and cell fate determination of hematopoietic stem cells, as well as in maturation processes and homeostasis of megakaryocytes and erythrocytes. In addition, NRF2 activation has been reported to suppress the production and secretion of inflammatory cytokines, thereby exerting anti-inflammatory effects. An NRF2 inducer, BG-12, was recently approved as a drug for multiple sclerosis. In contrast, in acute myeloid leukemia, the leukemia cells reportedly have higher NRF2 mRNA levels that lead to an increase in NRF2 protein abundance, by which these cells acquire high resistance to anticancer drugs. Therefore, both NRF2 activators and inhibitors are promising agents for the development of effective therapies for chronic inflammation and leukemia, respectively.

The leukemia stem cell (LSC) model has received considerable attention in the past 20 years with the identification of rare cell populations expressing stem cell markers in leukemia cell populations. LSCs are thought to be responsible for leukemia initiation, recurrence, and drug resistance, thus being regarded as excellent targets for developing curative therapies. However, several features of LSCs have recently been challenged. It has become increasingly evident that LSC phenotypes vary among patients. Technical variation of xenograft assays also affects the results, with a trend for more immunodeficient strains allowing the engraftment of variable LSC populations. Studies using mouse leukemia models have shown that not all leukemias are driven by rare and primitive LSCs, instead containing a large population of LSCs expressing mature markers. In addition, recent insights have highlighted genetic variations as important sources of tumor heterogeneity, indicating that the LSC model may not necessarily explain the heterogeneity observed in some leukemias. Nevertheless, several lines of evidence still suggest the existence of primitive LSCs that are associated with therapeutic resistance and poor prognosis in leukemia. This article summarizes current knowledge of LSCs and discusses the challenges ahead.