Hematopoietic stem cells (HSCs) are characterized by their ability to self-renew and differentiate into all blood lineage cells. The fate decisions of HSCs (self-renewal versus differentiation) are made through the process of cell division and are often compared to "birth" and "death". Stem cells give rise to undifferentiated stem cells (birth) or differentiate into progenitor cells (death). This process is regulated by asymmetric/symmetric divisions of HSCs. It has been proposed that fate determination occurs as a stochastic process and that individual stem cell dynamics are randomly regulated. The behavior of HSCs is known to be regulated by the cell intrinsic factor and extrinsic (microenvironmental) stimuli. Therefore, it is possible that the signals from a specific microenvironment (niche) have the potential to control or modulate stem cell dynamics. This review focuses on the functions of the HSC niche and the application of single cell analysis for understanding the mechanisms underlying the HSC decision-making process.

Epigenetic marks, such as histone modifications or DNA methylation, regulate tissue specific gene expression by affecting the structures and accessibility of chromatin or DNA. Epigenetics, the molecular mechanisms regulating the epigenome, would therefore be critically involved in development and cell differentiation versus proliferation. Histone modifications include methylation, acetylation, phosphorylation and ubiquitination of specific lysine, arginine or serine residues on histone tails, and each modification has its own specific effect on gene expressions. Modification of histones is accomplished by multimeric protein complexes including polycomb and trithorax group proteins. Regulation of DNA methylation is another mechanism of epigenetic regulation, which is achieved by DNA methyltransferase (DNMT) and TET family proteins. Methylation of cysteine residues on DNA generally leads to transcriptional repression, and oxidation of methylated cysteines provides another type of molecular mark on DNA that regulates gene expression. Next generation sequencing of tumor genomes has uncovered recurrent somatic mutations of epigenetic genes such as DNMT3A, TET2, and ASXL1 in hematologic malignancies, showing that epigenetic dysregulation is a critical step leading to the transformation of hematopoietic cells. Rigorous integrated functional analyses of mutated epigenetic genes are currently underway, and are anticipated to lead to the development of novel molecularly targeted therapies for hematologic malignancies.

Epidemiological studies suggest that exposure to prenatal stressors, including malnutrition, maternal immune activation (MIA), and adverse life events, is associated with increased risks of schizophrenia, autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD). However, the underlying pathophysiological mechanisms are unclear. The first trimester of pregnancy is particularly a vulnerable period. During this period, the self-renewal of neural stem cells and neurogenesis vigorously occur, and synaptic connections are partially formed in the telencephalon. Disturbance of this neuronal proliferation and migration during the first trimester may underlie the increased susceptibility to these disorders. Epigenetic modifications, such as DNA methylation and histone modification, are critical mechanisms for regulating gene expression. They can be affected by stress and are associated with an increase in susceptibility to schizophrenia and developmental disabilities. Injection of polyinosinic-polycytidylic acid or lipopolysaccharide induces MIA, enhances the expression of proinflammatory cytokines, and leads to the activation of microglia and the subsequent epigenetic modification of neurons or glia in the offspring. Furthermore, maternal high-fat diet and obesity similarly induce MIA and therefore may increase the risk of developmental disabilities. In addition, maternal stress reprograms the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the stress response in the offspring. Thus, exposure to prenatal stress may increase the susceptibility to schizophrenia, ASD, or ADHD in the offspring through epigenetic modifications, MIA, and alteration of the HPA axis.

A 58-year-old male underwent right lung transplantation from a brain-dead donor, after which acute rejection developed that was resistant to steroid pulse therapy. Rabbit-derived anti-thymocyte globulin (rATG) therapy was successful for controlling the rejection. However, following that therapy, the patient was affected by an opportunistic infection and suffered from repeated empyema. It is important to pay attention to immunosuppressive agent levels in blood following treatment, because ATG is a potent immunosuppressive drug and its effects can continue for more than 6 months after administration.

The difficulty in obtaining a sufficient number of functional dendritic cells(DCs)is a well-known serious problem in DCbased immunotherapy. Therefore, we used induced pluripotent stem cell-derived DCs(iPSDCs). We have reported that mouse iPSDCs are equivalent to BMDCs, in terms of maturation and antigen presentation. In this study, the antitumor immune response of human iPSDCs expressing the carcinoembryonic antigen was examined, to determine its clinical application in gastrointestinal cancer. Human iPS cells were established from healthy human fibroblasts using a Sendai virus vector, and human iPSDCs were differentiated under a feeder-free culture. Additionally, the surface marker expression, cytokine production, and migratory capacity of human iPSDCs were equivalent to those of monocyte-derived DCs(MoDCs). After 3 cycles of stimulation of autologous PBMCs by genetically modified DCs, the 51Cr-release assay was performed. The lymphocytes stimulated by iPSDCs-CEA showed cytotoxic activity against LCL-CEA and CEA652-pulsed LCL, but showed no cytotoxicity against LCL-LacZ. In addition, they showed cytotoxic activity against CEA-positive human cancer cell lines, MKN45 and HT29, but showed no cytotoxicity against CEA-negative human cancer cell line MKN1. In conclusion, CEA-specific CTLs responses could be induced by iPSDCs-CEA. This vaccination strategy may be useful in future clinical applications of cancer vaccines.

Induced pluripotent stem cells (iPSCs) are not only a valuable resource for regenerative medicine, but also a promising tool for disease modeling and drug discovery. Patient-specific iPSCs harboring disease-specific mutations are extremely useful for investigating disease mechanisms and novel treatment approaches. In the field of hematology, attempts to establish iPSCs from tumor cells such as those of leukemia or myelodysplastic syndrome (MDS) were largely unsuccessful because proper reprogramming processes were hampered by their extensive genetic alterations. In contrast, congenital disorders caused by a single genetic mutation are ideal candidates for deriving iPSCs. We have been investigating the molecular mechanisms underlying leukemia and MDS by implementing iPSC technology. Familial platelet disorder (FPD) is a rare autosomal dominant disorder characterized by thrombocytopenia and a high propensity for developing acute leukemia, which is caused by heterozygous mutation of RUNX1. We have successfully established iPSCs from three distinct FPD pedigrees and examined the responsible defect during hematopoietic development. This system will serve as a novel unprecedented platform for prospectively studying hematologic disorders using human cells.

The aim of stem cell therapy for Parkinson's disease (PD) is to reconstruct local synapse formation and/or induce the release of dopamine and cytokines from grafted cells in the putamen. Fetal ventral-midbrain cells reportedly relieve the neurological symptoms of PD patients. However, induced pluripotent stem cells (iPSCs) are expected to provide an alternative donor cell population because of their capacity for self-renewal and pluripotency. A protocol to generate dopaminergic (DA) neurons from iPSCs has been developed, and human ESCs were proven to function in the brains of rat and monkey PD models. We have developed a method of isolating DA neuron progenitors as a donor cell population, which allows safe and efficient transplantation.

Antibody-based anti-cancer immunotherapy was recently recognized as one of the truly effective therapies for cancer patients. Antibodies against cell surface cancer antigens, such as CD20, and also those against immune-inhibitory molecules called "immune checkpoint blockers", such as CTLA4 or PD1, have emerged. Large-scale clinical trials have confirmed that, in some cases, antibody-based drugs are superior to conventional chemotherapeutic agents. These antibody-based drugs are now being manufactured employing a mass-production system by pharmaceutical companies. Anti-cancer therapy by immune cells, i.e. cell-based immunotherapy, is expected to be more effective than antibody therapy, because immune cells can recognize, infiltrate, and act in cancer tissues more directly than antibodies. In order to achieve cell-based anti-cancer immunotherapy, it is necessary to develop manufacturing systems for mass-production of immune cells. Our group has been studying immunotherapy with myeloid cells derived from ES cells or iPS cells. These pluripotent stem cells can be readily propagated under constant culture conditions, with expansion into a large quantity. We consider these stem cells to be the most suitable cellular source for mass-production of immune cells. This review introduces our studies on anti-cancer therapy with iPS cell-derived dendritic cells and iPS cell-derived macrophages.

Tumor immunotherapy, especially tumor antigen specific T cell therapy, is currently attracting attention. However, a critical issue still awaits resolution; it is difficult to efficiently expand tumor antigen-specific T cells. To solve this problem, we are now utilizing iPS cell technology. When iPS cells are established from tumor antigen specific T cells, T cells regenerated from these iPS cells are expected to express the same TCRs as the original T cells. In line with this concept, we succeeded in regenerating tumor antigen specific cytotoxic T cells. The regenerated T cells exhibited TCR specific killing activity comparable to that of the original cells, and were able to kill leukemia cells in an antigen-specific manner. We are currently endeavoring to apply this method clinically. In the future, we intend to establish an allogeneic transfusion system, in which various tumor antigen specific T-iPS cells from a wide range of HLA haplotype homozygous donors will be lined up as a "T-iPS cell bank", with the aim of making off-the-shelf tumor immunotherapy a reality.

Hematopoietic stem cells (HSCs) have unique functional properties, including self-renewal and multi-lineage differentiation potential, and are thought to be fully responsible for lifelong hematopoiesis. However, recent studies have shown that HSCs divide much more slowly than thought, and, therefore, that daily hematopoiesis is maintained not by HSCs but by hematopoietic progenitors with limited self-renewal. When hematopoietic stress such as an infection occurs, hematopoietic production is at high demand at the site of infection. To meet hematopoietic needs, HSCs are also presumably recruited to orchestrate hematopoiesis. The beneficial and detrimental effects of inflammation on HSC function and the associated hematopoietic regulation are discussed herein, by summarizing recent findings.

Adult hematopoietic stem cells (HSCs) reside in bone marrow and are maintained in a dormant state within a special microenvironment, their so-called "niche". Detaching from the niche induces cell cycle progression, resulting in a reduction of the reconstitution capacity of HSCs. In contrast, fetal liver HSCs actively divide without losing their stem cell potentials. Thus, it has been unclear what types of cellular responses and metabolic changes occur in growing HSCs. We previously discovered that HSCs express relatively low levels of endoplasmic reticulum (ER) chaperone proteins governing protein folding, making HSCs vulnerable to an elevation of stress signals caused by accumulation of un-/misfolded proteins (ER stress) upon in vitro culture. Interestingly, fetal liver HSCs do not show ER stress elevation despite unchanged levels of chaperone proteins. Our latest studies utilizing multiple mouse models revealed that in the fetal liver bile acids as chemical chaperones play a key role supporting the protein folding which results in the suppression of ER stress induction. These findings highlight the importance of ER stress regulations in hematopoiesis.

A 48-year-old man was transferred to our emergency room because of sudden-onset epigastric pain and nausea. Abdominal contrast-enhanced computed tomography (CT) showed splenomegaly with splenic infarction and intra-abdominal bleeding, suggestive of splenic rupture. An emergent open splenectomy was performed. His spleen was markedly swollen and showed continuous bleeding due to a laceration. On histopathological examination, his spleen was filled with abnormal tumor cells. He was diagnosed as having mantle cell lymphoma based on the findings of immunohistochemical and cytogenetic analyses of the spleen. Mantle cell lymphoma cells were identified in the bone marrow and ileum, and he was determined to be in stageIVA by positron emission tomography (PET)-CT. He was administered rituximab combined with hyper-CVAD/MA chemotherapy (R-hyper-CVAD/MA regimen). After two courses of the R-hyper-CVAD/MA regimen, he achieved complete response, as confirmed by PET-CT. He received four courses in total of the R-hyper-CVAD/MA regimen, followed sequentially by high-dose chemotherapy and autologous peripheral blood stem cell transplantation (auto-PBSCT). He is currently alive and free of disease. This is the 10(th) report of a mantle cell lymphoma case with spontaneous splenic rupture. We herein review previous reports and emphasize the importance of awareness of hematological malignancies when encountering a case with spontaneous splenic rupture.

In addition to the discovery that mature cells can be reprogrammed to become pluripotent stem cells(iPS cells), the technical innovations of big-data analyses as well as the cutting- edge technologies such as nuclear reprogramming technique and genome-editing system are emerging a big paradigm shift in the field of regenerative medicine and aging. This is bonafide a kind of the molecular biological movement of the Renaissance to answer the question of 120 years ago "D'ofi Venons Nous Que Sommes Nous Oi Allons Nous", a testament of Paul Gauguin. These technologies enable us, particularly inexhaustible researchers with challenging spirits, not only to dynamically, qualitatively and visually systematically understand underling mechanisms of single gene, single molecule, single cell and their complicated networks in vivo with broadly combining them from cells to organs and individuals', but also to pursue the mechanistic insight into "Life, Aging, Disease, and Death" and thereby con- trol them. We herein review about recent hot topic findings focused on regenerative medicine, cellular senescence & aging as well as aging-related disease, and then discuss the functional interconnection between reprogramming process and senescence signal.

Aging-related pathophysiology is extremely associated with altered potential of stem cells. The changes of HSCs during aging have been studied for decades prior to other tissue stem cells, and many mechanisms are reported to be involved. Recently epigenetic regulations are shed light as central to maintaining stem cell function and epigenetic dysregulation contrib- utes to the functional decline of stem cells during aging. Alterations which arise in stem cells are not only perpetuated and amplified in stem cell pool through self-renewal, but are heritably transmitted to differentiated progenies. Such alterations can be clonally expanded and establish clonal hematopoiesis already in healthy elderly, and can promote subsequent occurrence of hematopoietic diseases. This review focuses on recent studies examining epige- netic regulation of HSCs in aging.

Telomeres are vital for chromosome end protection against activation of DNA damage response. Telomere attrition leads to cell cycle arrest, which underlies cellular senescence and can restrict tissue replenishment. Although stem cells express telomerase reverse tran- scriptase, which elongates telomeric DNA, its activity is not enough to fully compensate for chronic telomere shortening. Growing lines of evidence, including telomerase knockout mouse models and human genetic diseases, suggest that a decline in the cellular renewal capacity of stem cells is a consequence of such telomere shortening. These findings highlight the critical importance of telomere protection control for human aging process, and may lead to new strategies for healthy life extension.

We are living in an era characterized by an unprecedented scientific and technological revolution, which is also affecting both the health and medical fields. The revolution surrounding the cancer field is drastically changing not only the research and development sector, but also the manner in which malignancies are diagnosed and treated. This is due to achievements in genome, molecular immunology, and stem cell research. Here are some examples of molecular targeted therapy drugs. The targeted drug crizotinib, developed after the discovery of driver genes and genotype identification, opened up a newera of genome clinical sequencing. Mogamulizumab not only targets the chemokine receptor CCR4 but also modifies host antitumor immunity by suppressing Tregs. Trametinib is a molecular targeted therapy drug that controls molecules associated with the control system responsible for tumor maintenance. The creation of an assay system resulted in a breakthrough in this field, which led to the development of trametinib and crizotinib. The checkpoint inhibitor nivolumab acts on the immune system of the host and promotes tumor targeting. As exemplified by these developments, the paradigm of cancer drug therapy is changing from a probabilistic approach(ie, administering a general anticancer drug), to a deterministic approach(ie, administering the most adequate drug after diagnosing the specific mechanisms responsible for tumor generation, sustenance, and progression). The latter requires a drastic change in the way clinical trials are performed. Thus, we are now entering a newphase: the era of precision medicine. Herewe discuss the present state of the cancer medical revolution and the academic progress in research and development and cancer therapy in our country.