Induced pluripotent stem (iPS) cells are an attractive cell source in regenerative medicine; however, some problems must be overcome to improve clinical applications. iPS cells generated using the genomic integration method increase the risk of tumor generation because of transgene reactivation and the disruption of endogenous genes. The somatic cell sources of iPS cells also affect teratoma formation. Therefore, it is important to select a suitable cell source from among adult somatic cells, to generate iPS cells using a transgene insertion-free method, and to screen for good iPS clones that do not contain any differentiation-resistant cells after differentiation induction. Recently, we reported a method for obtaining high-quality iPS cells using purified mesenchymal stem cells (MSCs). In this report, we produced genomic integration-free iPS cells from adult tissues, purified MSCs, and tail tip fibroblasts using the Sendai virus. Then, we evaluated the residual undifferentiated cells in secondary neurospheres generated from retroviral induction iPS cell lines and non-integration iPS cell lines derived from adult MSCs. As a result, we could generate integration-free iPS cells only from MSCs. Nevertheless, some iPS cell lines generated by the non-integration method contained undifferentiated cells. Interestingly, the integration-free iPS cells that could not differentiate correctly showed a higher side scatter (SSC) intensity than the other ES/iPS cells. Some somatic cell-derived iPS cells had a higher SSC intensity, and these cells also could not differentiate normally. Our findings suggested that an SSC intensity analysis may be efficient method for evaluating individual iPS cells before their use in therapies.

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Hematopoietic stem cells (HSCs) are capable of self-renewal and multi-lineage differentiation, which are characteristics that enable them to maintain the stem cell population and produce large numbers of blood cells. Quiescent mammalian adult HSCs localize within the bone marrow niche, primarily in the endosteal region of the trabecular bone. These cells scarcely participate in the cell cycle, but are instead maintained by assorted niche cells within the bone marrow, including mesenchymal stem cells (MSCs). This review summarizes the crucial role(s) that MSCs play as niche cells for the support of HSCs.

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Mesenchymal stem cell (MSC) is one of somatic stem cells useful for regenerative medicine. This type of stem cell can be easily isolated form adult tissues such as bone marrow (BM). However, MSC isolation is difficult in elder patients and self-MSC cannot be prepared quickly. ES cells, a pluripotent stem cells (PSC), have recently been characterized as a novel source of MSCs. Furthermore, medical progress found a new method of self-PSC generation in which somatic cells can be reprogrammed into pluripotent stem cells, namely induced pluripotent stem cells (iPSCs). In this review, I provide and discuss our recent results regarding to ES/iPS cell-derived Mesodermal cells and MSCs. Based on this information; I will describe future perspectives for the utility of MSCs and ES/iPS cell-derived MSCs.

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Tooth loss or damage, such as that caused by dental caries and periodontaldisease, can cause fundamental problems with oral functions. The development ofregenerative therapy for tooth tissue repair and whole-tooth replacement is currentlyconsidered a novel treatment with the potential to fully recover tooth function. Severalmesenchymal stem cell-like cell types have been identified in oral tissues. These cellsare thought to be good candidate cell sources for tooth tissue regeneration therapiesbecause they exhibit the ability to differentiate into tooth tissues in vitro and in vivo.Whole-tooth replacement therapy is regarded as an important model system for thedevelopment of the concept of organ regeneration. A novel three-dimensional in vitro cell manipulation method, designated as an organ germ method, has been developed torecapitulate organogenesis. This method involves cell compartmentalization betweenepithelial and mesenchymal cells at a high cell density to mimic the multicellularassembly and epithelial-mesenchymal interactions. The bioengineered tooth germgenerates a structurally correct tooth in vitro, and erupted successfully with correcttooth structure when transplanted into a tooth socket in the oral cavity. We could alsogenerate a size-controlled bioengineered mature tooth unit composed of periodontalligament and alveolar bone. The bioengineered tooth unit was successfully engraftedinto an adult jaw through bone integration. These bioengineered teeth were able toperform physiological tooth functions such as mastication, periodontal ligamentfunction and response to noxious stimuli. Here, we review recent studies of toothtissue-derived mesenchymal stem cells and the technologies underpinning toothregenerative therapy.

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Over the last few years, the mesenchymal stromal compartment of the bone marrow has regained interest. The main reason for this resurgence is the recognition of their immunomodulatory properties and their prominent role in the maintenance and regulation of hematopoiesis. This has simultaneously prompted preclinical and clinical studies trying to take advantage of these properties and, at the same time, basic studies that have tried to dissect the bone marrow stromal compartment and the specific functions that different stromal cells have in the regulation of hematopoiesis and immunity. In this minireview we will summarize our contributions to the functions of mesenchymal stem cells in regulating hematopoietic stem cells. By putting them in a broader context, we will discuss the emerging role of mesenchymal stem cells as key integrators of neuro-endocrine signals, able to couple whole-organism demands to fine-tuned responses in remote stem cell niches.

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Since the monumental publication in 1998 by Pittenger et al., mesenchymal stem cells (MSCs) have been a center player of regenerative medicine and now a number of clinical trials using MSCs have been conducted in various fields of tissue regeneration including those of bone. It cannot be denied that due to enthusiastic clinical demanding, clinical application of MSCs has launched with little knowledge concerning the nature of native MSCs. Recent advances, however, have gradually revealed enigmatic biological properties of MSCs, which subsequently requires the reconsideration of minimum criteria of this type of stem cells. Plastic adherence was no more an absolute requirement of MSCs, and there seemed to be CD34⁺ MSCs. In addition, in vitro multidirectional property does not guarantee such property in vivo. As a more fundamental issue, cell-of-origin of MSC may be not single, and there seemed to be at least ectodermal (neural crest) MSCs and mesoderm (perivascular) MSCs. Accumulation of preclinical and clinical data has also revealed the role of MSCs in bone regeneration. Against to the initial expectation, the role of MSCs as cell sources to participate bone regeneration seemed to be less significant than those as producer of materials to induce bone regeneration by host cells. The later role may open a new venue of regenerative medicine, which may be called cell-free cell therapy. Understanding of these important features and function of MSC will greatly improve the value of MSCs and promote the proper application of these cells in bone repair and regeneration.

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Interleukin-6 (IL-6), originally identified as a B cell stimulatory factor-2, is a typical cytokine featuring redundancy and pleiotropic activity. A transient expression of IL-6 participates in host defense against acute environmental stress such as infections and injuries by activating immune responses, hematopoiesis and acute phase reactions. However, its abnormal, persistent production plays an important pathological role in the development of various autoimmune inflammatory diseases, so that it was hypothesized that IL-6 blockade would constitute a novel strategy for the treatment of such diseases and to this purpose tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, was developed. Clinical trials have indeed proved the efficacy and tolerable safety of tocilizumab for patients with moderate to severe rheumatoid arthritis, and it is now used as a “made-in-Japan” innovative biologic for rheumatoid arthritis in more than 90 countries worldwide, as well as for patients with Castleman's disease and systemic and polyarticular juvenile idiopathic arthritis. Moreover, favorable results of recent clinical trials or case reports of off-label use with tocilizumab indicate that it is likely to be broadly applicable for the treatment of various autoimmune inflammatory diseases. Its wider application for various diseases as well as clarification of the mechanism(s) through which IL-6 blockade becomes clinically efficacious and of the etiology of dysregulated persistent IL-6 production in such diseases are important issues for future studies.

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Acetaminophen (APAP) hepatotoxicity because of overdose is the most frequent cause of acute liver failure. The mechanisms of APAP hepatotoxicity are dominated by intracellular events including the formation of a reactive metabolite, hepatic glutathione depletion and protein binding. In response to overdose of APAP treatment, the liver elicits a healing process characterized by proliferation of hepatocytes, removal of necrotic tissue, and restoration of the hepatic microvasculature. However, the mechanisms of repair of the tissue damage during APAP hepatotoxicity are poorly understood. Vascular endothelial growth factor (VEGF) and its receptors, VEGFR1 and VEGFR2, promote the repair and regeneration of the liver after acute insult including liver resection and toxicants. This mini review focuses on the role of VEGF/VEGFRs signaling in liver injury and hepatic tissue repair during APAP hepatotoxicity.

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Periodontal diseases are highly prevalent inflammatory diseases that lead to a destruction of tooth-supporting tissues, such as the periodontal ligament, alveolar bone and cementum, and ultimately result in tooth loss. Conventional treatment for periodontal diseases is the mechanical removal of the periodontal biofilm, which although effective in reducing inflammation in lesion sites, dose not allow regeneration of lost tissues. Therefore, it is important that new therapeutic procedures that encourage the regeneration of periodontal tissues destroyed by periodontal disease will be established. In recent years, the efficacy of topical application of recombinant cytokines for periodontal regeneration has been investigated. This review focuses on the biological activities of FGF-2 in promoting periodontal tissue regeneration.

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