During past decades, cancer vaccine therapy has been focused on only the activation of CTL, but its therapeutic effect was not successful though long SD was induced. The failure of cancer vaccine is derived from (i) the existence of a strong tumor escape mechanisms and (ii) the ignorance of helper T cell activation. We have proposed that Th1-dominant immunity played a critical role for overcoming immunosuppressive tumor-escape mechanisms to induce tumor-specific CTL, which are essential for the complete cure of tumor and prevention of tumor recurrence. To apply these basic findings, we started a clinical trial of a novel cancer vaccine/cell therapy (Th1 cell therapy) using H/K-HELP of MAGE-A4 or Survivin cancer antigen. In phase I study, H/K-HELP consisted of both killer and helper epitopes and Th1 adjuvants (OK-432 and Montanide) were subcutaneously administered into cancer patients 4 times at 2 wks intervals. Both MAGE-A4-H/K-HELP and Survivin-H/K-HELP cancer vaccine induced cancer-specific Th1 and Tc1 immune responses and cancer-specific C-fixing antibodies (IgG1 and IgG3) in cancer patients. Moreover, Survivin-H/K-HELP vaccination induced a complete regression of chemo and radio-resistant lateral deep cervical node recurrence of triple-negative breast cancer. H/K-HELP vaccination with Th1 adjuvants or its combination with Th1 cells will become a promising cancer vaccine/cell therapy of human cancer.

Hematopoietic stem cells (HSCs) and their progeny are thought to be regulated by special microenvironments, termed niches in the bone marrow during homeostasis. However, the identity and function of these hematopoietic niches remains unclear. It has been reported that HSCs are in contact with osteoblasts lining the bone surface and osteoblasts act as niches for HSCs (endosteal niche) ; however, other studies suggest that few HSCs reside in the endosteal niche. In contrast, most HSCs are shown to be in contact with endothelial cells (vascular niches) and/or primitive mesenchymal cells, including CXCL12-abundant reticular (CAR) cells or Nestin-expressing cells, which have ability to differentiate into adipocytes as well as osteoblasts. Recent in vivo studies revealed that CAR cells acted as niches for hematopoietic stem and progenitor cells (HSPCs) and that endothelial cells and Nestin-expressing cells acted as niches for HSCs. In addition, marrow nonmyelinating schwann cells might be involved in the maintenance of HSCs. Here we review candidate niches for HSCs and hematopoiesis in the marrow.

The immune and skeletal systems are closely related through a number of shared regulatory molecules including cytokines. Studies on bone destruction associated rheumatoid arthritis (RA) as well as identification of the various bone phenotypes found in immune-compromised genetically modified mice have highlighted the importance of the interplay between the two systems, and promoted the new interdisciplinary field of "osteoimmunology" . Accumulating evidence has indicated that bone destruction associated with RA is caused by the enhanced activity of osteoclasts, resulting from the activation of a unique helper T cell subset, "Th17 cells" . The osteoimmunological insight is of growing importance in clinical applications. Furthermore, recent studies has suggested the relationship between bone cells and hematopoietic stem cells in bone marrow. Various cell types in bone marrow are expected to control bone homeostasis, calcium metabolism and hematopoiesis by mutually affecting each other. Osteoimmunology becomes the viewpoint indispensable for not only bone and mineral research but also immunological research.

Morbidity and mortality in heart failure (HF) remain high in developed countries. Cardiac regenerative therapy with stem cells has the potential to improve the treatment of HF. Several cell sources have been investigated for cardiac cell transplantation therapy. The most representative cell sources are bone marrow stem cells, skeletal myoblasts, and cardiac progenitor cells. Skeletal myoblasts raise the issue of arrhythmo-genicity. Regenerative cardiomyocytes derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) are the most promising, because ESCs and iPSCs can potentially generate both contraction recovery and electromechanical coupling with host cardiomyocytes. The functional mechanism of myocardial cell transplantation therapy may be cardiac differentiation, cytokine effects, neovascularization, and intrinsic cardiac progenitor differentiation. It is critical to establish the differentiation protocol from hESCs and hiPSCs to cardiomyocytes. The survival of transplanted cells is also very important. The clinical application of myocardial cell therapy is anxiously awaited for the treatment of HF.

Transplantation of the small intestine is rarely performed clinically for the treatment of short bowel syndrome because it is difficult to overcome the powerful rejection response. In contrast, regenerative medicine to restore self-organization is expected to overcome this problem. Here we demonstrate that mouse induced pluripotent stem (iPS) cells have the ability to organize a gut-like organ with motor function in vitro in a hanging drop culture system. This "induced gut (iGut)" exhibited spontaneous contraction and highly coordinated peristalsis accompanied by the transport of contents. The iGut was composed of all the enteric components of the three germ layers: epithelial cells (endoderm); smooth muscle cells (mesoderm); interstitial cells of Cajal (mesoderm); and enteric neurons (ectoderm). This study not only contributes to the understanding of the mechanisms of incurable gut disease through disease-specific iPS cells but also facilitates the clinical application of patient-specific iPS cells for novel therapeutic strategies such as patient-specific organ regenerative medicine in the future.

L-Glutamate (Glu) and γ-aminobutyric acid (GABA) has been thought to be an excitatory/inhibitory amino acid neurotransmitter in the mammalian central nervous system (CNS). Limited information is available in the literature with regard to an extracellular transmitter role of Glu and GABA in peripheral neuronal and non-neuronal tissues, whereas recent molecular biological analyses including ours give rise to a novel function for Glu and GABA as an autocrine and/or paracrine factor in a variety of cells derived from mesenchymal stem cells, in addition to other peripheral tissues including pancreas, adrenal, and pituitary glands. Emerging evidence suggests that Glu and GABA could play a dual role in mechanisms underlying maintenance of cellular homeostasis as a neurotransmitter in the CNS and as an extracellular signal mediator in peripheral autocrine and/or paracrine tissues. In this review, therefore, we summarized the possible signaling by Glu and GABA as an extracellular signal mediator in mechanisms underlying maintenance of cellular homeostasis in mesenchymal stem cells, osteoblasts and chondrocytes.