Down syndrome (DS) is caused by trisomy for human chromosome 21. Individuals with DS commonly exhibit mental retardation, which is associated with abnormal brain development. In the neocortex of the DS brain, the density of neurons is markedly reduced, whereas that of astrocytes is increased. Similar to abnormalities seen in DS brains, mouse models of DS show deficits in brain development, and neural progenitor cells that give rise to neurons and glia show dysregulation in their differentiation. These suggest that the dysregulation of progenitor fate choices contributes to alterations in the numbers of neurons and astrocytes in the DS brain. Nevertheless, the molecular basis underlying these defects remains largely unknown. We showed that the overexpression of two human chromosome 21 genes, DYRK1A and DSCR1, contributes to suppressed neuronal differentiation of progenitors in the Ts1Cje mouse model of DS. In addition, the effect of DYRK1A and DSCR1 overexpression on neuronal differentiation is mediated by excessive attenuation of the transcription factor NFATc. Additionally, we demonstrated that an increased dosage of DYRK1A contributes to elevated potential of Ts1Cje progenitors to differentiate into astrocytes and enhanced astrogliogenesis in the Ts1Cje neocortex. Further, we linked the increased dosage of DYRK1A to dysregulation of STAT, a transcription factor critical for astrogliogenesis. Together, our studies identify critical pathways responsible for the proper differentiation of neural progenitors into neurons and astrocytes, with direct implications for the anomalies in brain development observed in DS.

Heart disease is one of the leading causes of death in the developed countries and various physical conditions in heart failure attribute to the impaired physical activities, which promotes aging. The principle cause of heart failure is the loss of self-renewal ability of cardiomyocytes in various injuries such as myocardial infarction. The replacement of injured tissues with the regenerated human myocardial tissues using technologies on tissue engineering and iPS cell will provide us the novel therapeutic strategy for heart failure and the related aging issues.

Hematopoietic stem cell transplantation (HSCT) involves some serious transplant-associated complications (TACs) or vascular disorders, such as veno-occlusive disease (VOD), thrombotic microangiopathy (TMA), and graft-versus-host disease (GVHD). VOD is related to a clinical syndrome characterized by tender hepatomegaly, jaundice, fluid retention, and unexplained weight gain. When TMA is described in patients who have undergone HSCT, it is often implied that the clinical diagnosis of TMA is similar to that of thrombotic thrombocytopenic purpura. Therefore, levels of cytokines, chemokines, and soluble molecules are useful biomarkers for VOD and TMA after HSCT. Acute GVHD (aGVHD) occurs in the early period after transplantation and is initiated by alloreactive donor T cells. The mechanisms whereby immune responses trigger this post-transplantation condition remain unclear, but endothelial cell function might play a role in this. The authors investigated the expression of endothelial cell activation markers such as sE-selectin, sVCAM-1, PAI-1, and microparticle in patients undergoing allogeneic HSCT. Levels of endothelial cell activation markers were significantly higher in 143 patients who developed aGVHD than in those who did not develop aGVHD. Moreover, patients who received rTM exhibited a significantly lower frequency of aGVHD and reduced levels of endothelial cell activation markers. These findings suggest that endothelial cell activation might be linked to TAC and that rTM may, at least in part, act to prevent TAC through its effect on endothelial cells.

A 53-year-old man diagnosed with adult T-cell lymphoma (ATL) was treated with mLSG15 chemotherapy and achieved a first complete remission. Subsequently, a liver tumor emerged that was pathologically diagnosed as ATL (first relapse). A second remission was achieved after local irradiation and four cycles of mogamulizumab treatment. The patient received peripheral blood stem cell transplantation (HSCT) from a one haplotype HLA-mismatched daughter after total body irradiation and the administration of fludarabine as a myeloablative conditioning regimen, followed by post-transplant cyclophosphamide. While subsequent acute graft-versus-host disease (GVHD) was never more than Grade I, severe chronic GVHD (cGVHD) developed in the oral cavity and skin that was resistant to escalated doses of cyclosporine and prednisolone. The patient subsequently had a second relapse of ATL as a subcutaneous mass and eventually died of disease progression. Mogamulizumab is a humanized monoclonal IgG that targets CC chemokine receptor 4 (CCR4) and is a key treatment option for relapsed ATL. It reportedly increases the risk of acute GVHD after HSCT due to the depletion of CCR4-positive regulatory T-cells; however, information on its impact on cGVHD is unavailable. Here, we discuss the potential risks and benefits of mogamulizumab, particularly in a haploidentical donor setting during a HSCT for ATL.

A 64-year-old man was diagnosed with acute myeloid leukemia M2 (FLT3-ITD-positive). After induction chemotherapy and four courses of consolidation therapy, he underwent umbilical cord blood transplantation (CBT) in his first remission. He developed acute graft-versus-host disease (skin stage 2) after successful engraftment. On post-transplantation day 147, he was admitted to the hospital suffering from pneumonia. During the treatment, drastic thrombocytopenia was observed on day 251. Both platelet-associated immunoglobulin G and platelet antibody producing B cells were detected, and he was diagnosed with immune thrombocytopenia (ITP). Treatment with prednisolone (1 mg/kg/day), eltrombopag (25 mg/day), and intravenous immunoglobulin (400 mg/kg) was commenced, but there was no improvement in his platelet count. After switching from eltrombopag to romiplostim (350 µg/week), and addition of cyclosporine, the platelet count rapidly elevated to 150,000/µl. ITP after allogenic stem cell transplantation is a rare complication, and it is often refractory to the 1st-line treatment such as steroids. Herein, we report successful treatment using a combination of romiplostim and an immunosuppressive agent in the case of treatment failure in ITP that developed after CBT.

The intestinal epithelium harbors stem cells at the bottom of crypts. Intestinal stem cells(ISCs)differentiate toward two alternative lineages of secretory or absorptive cells in a unidirectional manner. Studies have revealed factors that are indispensable for maintaining proliferation and differentiation of ISCs, which are provided from the surrounding environment. Additionally, several back-up systems compensating the sudden and massive loss of the ISC pool has been reported. Recent development of the three-dimensional culture system of ISCs in vitro has greatly contributed to elucidate these functional analyses of ISCs.

The pluripotent stem cells have a self-renewal ability and can be differentiated into theoretically all of cell types. The induced pluripotent stem (iPS) cells overcame the ethical problems of the human embryonic stem (ES) cell, and enable pathologic analysis of intractable diseases and drug discovery. The in vitro disease model using disease-specific iPS cells enables repeated analyses of human cells without influence of environment factors. Even though autoimmune diseases are polygenic diseases, autoimmune disease-specific iPS cells are thought to be a promising tool for analyzing the pathogenesis of the diseases and drug discovery in future.

Cancer-stem cells (or cancer-stem like cells, CSC) play an indispensable role in tumor initiation or tumor development in vivo. However, CSCs are resistant to conventional therapies including chemo/radiotherapy and a certain molecularly-targeted therapy, thereby are responsible for tumor relapse or metastasis in clinical settings. In this review, we focus on cytotoxic T-cell mediated immune responses against CSCs and discuss a challenge of targeting CSCs as well as the development of CSC-based cancer immunotherapy, which is an emerging and promising strategy toward a complete cure of quite a few types of cancers.

CD271 is common stem cell marker for the epidermis and dermis. We assessed a kinetic movement of epidermal and dermal CD271+ cells in the wound healing process to elucidate the possible involvement with chronic skin ulcers. Epidermal CD271+ cells were proliferated and migrated from 3 days after wounding. Purified epidermal CD271+ cells expressed higher TGFβ2 and VEGFα transcripts than CD271- cells. Delayed wound healing was observed in the aged mice compared with young mice. During the wound healing process, the peak of dermal CD271+ cell accumulation was delayed in aged mice compared with young mice. The expression levels of collagen-1, -3, -5, F4-80, EGF, FGF2, TGFβ1, and IL-1α were significantly increased in young mice compared with aged mice. Furthermore, purified dermal CD271+ cells expressed higher FGF2, EGF, PDGFB, and TGFβ1 gene transcripts than CD271- cells. These results suggested that epidermal and dermal CD271+ cells were closely associated with wound healing process by producing various growth factors. Epidermal and dermal CD271+ cells in chronic skin ulcer patients were significantly reduced compared with healthy controls. Thus, both epidermal and dermal stem cells can play an important role in wound healing process.

Human mesenchymal stromal/stem cells(MSCs)show a multiple biological characteristics including the immunomodulation, tissue regeneration and hematopoiesis-supportive capability. Cell therapy by the use of MSCs has been extensively explored for a variety of diseases. Several tissues/organs are clinically available for a source of MSCs, and isolated cells are culture-expanded and subsequently injected into patients systemically or locally. MSCs organize the tissue/organ environment they reside, and in bone/marrow, MSCs differentiate into osteoblasts(OBs)that contribute to bone remodeling. Intriguingly, cells that are in a differentiation stage between MSCs and OBs show a unique hematopoiesis-supportive capability, thereby pharmacological simulation with parathyroid hormone that skews MSCs towards such cells could be an alternative strategy for disease treatment.

More than 100 years ago, macrophages was discovered. So far, we thought that these are no subtype of macrophages in out body. However, recent studies of these cell types indicate that more than two types of macrophages are existed, and each cell types has inherent functions. In this review, we describe the functional diversity of various type of disorder-specific macrophages and its differentiation mechanism.

Allogeneic hematopoietic stem cell transplantation(allo-SCT)is curative therapy for various hematological diseases. Graft-versus-host disease(GVHD)and infection remain the main problems in allo-SCT. Gastrointestinal tract is targeted by GVHD. In intestinal GVHD, intestinal stem cells and Paneth cells reside at the base of crypts are damaged by donor T cells. These damage leads to disruption of intestinal mucosal barrier and intestinal dysbiosis, resulting in more exaggerated GVHD. Recently, we and others have reported that R-Spondin1 and interleukin-22 as factors regenerated intestinal tissue homeostasis in murine model of bone marrow transplantation. It is important to understand biology of various cells targeted by intestinal GVHD and develop novel methods to protect them from GVHD damage.

At steady state, hematopoietic stem cells(HSCs), the most undifferentiated cells in the hematological system, are kept quiescent in the cell cycle. Upon hematological stresses, including radiation, anti-cancer medication, infection, and transplantation, bone marrow HSCs enter the cell cycle and robustly repopulate the entire hematopoietic system via multi-lineage differentiation and self-renewal, partly due to the alteration of their surrounding microenvironment or niche. Such hematological repopulation activity is termed "stress hematopoiesis," an activity essential for homeostatic maintenance of blood production. Understanding stress hematopoiesis is also critical to establish efficient methods enabling expansion in vitro of HSCs, since forced activation of the cell cycle by cytokine supplementation induces a stress-like cellular state.

Recent advances in analysis technology have revealed that non-coding RNAs(ncRNA)that are not translated and function as RNA itself. It has been revealed that long ncRNA(lncRNA), which has more than and 200 nucleotides, is involved in the regulation of fate decision in neural stem cells. In this article, we introduce some functional lncRNAs regulating neural stem cells and discuss the future perspective about this field.

The hair follicle is a complex miniorgan of the skin and undergoes cycles of growth(anagen), apoptosis-mediated regression(catagen)and rest(telogen). Regeneration of the new hair shaft dependent on the activation of hair follicle stem cells(HFSCs), harboured in the bulge region. Using a hair follicle model, some molecular players that control the balance between HFSC maintenance and ageing-associated HFSC dysfunction have been identified. Here, we reviewed and discussed the recent findings of molecular characterization of HFSCs biology and pathology.

Adipose tissues are the major organ that controls systemic energy metabolism and maintain homeostasis by storing lipids, dissipating them as heat, and producing various adipokines. There are two major classes of adipocytes: white and brown adipocytes. White adipocytes store and release lipids, while brown adipocytes burn substrates to produce heat. In addition to classical brown adipose tissues consisting of brown adipocytes, cold exposure and β3 stimulation induce development of brown cell-like "beige" adipocytes in white adipose tissues. There appear to be multiple adipocyte progenitor cell populations of different developmental origins. In this article, we overview white and brown/beige adipocyte differentiation in development and obesity. Adipocytes differentiate in complex interplays with various stromal cells, including vascular, immune and neuronal cells. Elucidation of the cellular interplays would lead to identification of novel therapeutic targets for obesity and metabolic syndrome.

Adult skeletal muscle has its own stem cell population known as satellite cells. After muscle injury, quiescent satellite cells are activated and then proliferate and differentiate into mature skeletal muscle to ensure that muscle function is recovered. In our screen for myocyte differentiation-promoting factors, we noted markedly elevated expression of granulocyte-colony stimulating factor receptor(G-CSFR, encoded by csf3r)in the skeletal muscle developing area. Furthermore, G-CSFR was transiently expressed in regenerating myocytes of adult injured skeletal muscle, and extrinsic G-CSF supported short-term and long-term muscle regeneration in mouse model of skeletal muscle injury.

Bones support the body as part of the human musculoskeletal system. They also contain bone marrow, which is a site of hematopoiesis. Bone marrow mesenchymal stem cells play a vital role by regulating skeletal tissue formation and maintaining hematopoiesis. While the presence of bone marrow-derived mesenchymal stem cells has been indicated, they have yet to be fully understood in vivo. Recent studies using genetic mouse models revealed that perivascular stromal cells function as mesenchymal stem cells, and their differentiation status may vary during the early stage of life to adulthood. Furthermore, studies have investigated the underlying mechanisms that regulate the cell fate decision of mesenchymal stem cells. These findings could lead to the design of new therapeutic approaches for metabolic bone disease and hematopoietic disease.

Paroxysmal nocturnal hemoglobinuria (PNH) manifests by clonal expansion of mutant hematopoietic stem cells (HSCs) bearing a somatic mutation in the X-linked PIGA gene. PIGA mutations cause defective biosynthesis of GPI and cell surface deficiency of GPI-anchored proteins such as DAF and CD59, leading to intravascular hemolysis and thrombosis. These two major symptoms of PNH can be controlled by eculizumab, an anti-C5 monoclonal antibody. Bone marrow failure, the third major symptom of PNH, is autoimmune-mediated and contributes to the clonal expansion of GPI-defective HSCs by selectively attacking GPI-positive wild-type HSCs. GPI-defective erythrocytes, being protected from intravascular hemolysis by eculizumab, accumulate C3-derived fragments, C3b, iC3b, and C3dg, because of DAF deficiency and in turn become susceptible to CR3-mediated phagocytosis by spleen macrophages. Approximately 3% of Japanese patients with PNH are refractory to eculizumab therapy. Approximately 3% of Japanese people are heterozygous for a single nucleotide polymorphism that changes an amino acid near the eculizumab binding site. New therapeutic measures are needed to solve these issues.

Mast cells originate from hematopoietic stem cells and undergo terminal maturation in the extravascular tissues, in which they are ultimately resident. Mast maturation, phenotype, and function are dictated by the local microenvironment, which has a significant influence on the ability of mast cells to recognize and respond to stimuli. Activation of mast cells can lead to the release of three distinct classes of mediators, including preformed mediators stored in secretory granules, newly transcribed cytokines and chemokines, and de novo-synthesized bioactive lipid mediators. It is currently recognized that bioactive lipids such as arachidonic acid metabolites (prostaglandins and leukotrienes) released from mast cells modulate innate and adaptive immune responses both directly and indirectly through communication with other microenvironmental immune cells or stroma cells. Moreover, mast cells express a variety of lipid receptors and, if activated by bioactive lipids such as arachidonic acid, ω3 fatty acids, lysophospholipids, and their metabolites, can alter the release and production of other mediators including histamine, cytokines, and chemokines, and thereby alter homeostatic or pathophysiological responses. This review focuses on newly identified functional aspects of bioactive lipids with regard to their immune regulation and functional outcomes in both homeostasis and allergic disease.