Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for a majority of hematologic malignancies. However, this treatment procedure can still be associated with significant treatment-related mortality and morbidity, including regimen-related toxicity, graft-versus-host disease, and opportunistic infections. Recently, the advent of molecularly targeted therapy, such as tyrosine kinase inhibitors or antibody drugs, have changed the indications and techniques employed for allogeneic HSCT. In addition, as molecular pathogenesis of a variety of hematologic malignancies has become clear, it has been suggested that mutational profiling can potentially be used for risk stratification and to inform therapeutic decisions regarding patients with hematologic malignancies. Here, we review the knowledge regarding the current status and future directions for allogeneic HSCT in these backgrounds.

The application of iPS cells for diseases in the locomotive system includes the cell therapy using bone or cartilage cells and the understanding of pathogenesis and drug discovery for intractable diseases using patients' derived iPS cells. To promote these researches, the proper knowledge concerning the process from iPS cells to multipotential mesenchymal stromal cell (MSC) and terminally differentiated cells is inevitable. In addition, because there are several different ways to induce terminally differentiation, the biological quality of cells induced by each method should be compared in future.

Mesenchymal stem cells (MSCs) are important clinical applications in treating immune disorders due to their multipotency, immunosuppressive properties by production of cytokines. However, the majority of studies rely on an in vitro cell expansion phase, and the properties of MSCs in vivo are still unknown, because there is no specific marker for MSCs. The purpose of this review is to provide an update on our knowledge of MSCs isolation and their immunosuppressive properties, focusing on bone marrow-derived MSCs.

Mesenchymal stem cells (MSCs) have multi-differentiation potency, and enhance wound healing in various kinds of disease. Recently MSC not only differentiate into tissue-forming cells, but also secrete various kinds of cytokines and chemokines that are anti-apoptotic, immunomodulatory, angiogenic, and the cell-mobilizing to influence extracellular environment. In addition, we show that MSC has a novel intercellular communication mechanism. It hopes to suggest ways to make safer and reliable usage of MSC in bone regeneration.

Differentiation of mesenchymal stem cells to osteoblastic lineage cells is regulated positively by factors such as mechanical strain and parathyroid hormone, and is negatively regulated by factors including aging and glucocorticoids. Wnt/β-catenin pathway plays an important role in controlling the bifurcation of mesenchymal stem cell differentiation between osteoblastic and adipocytic lineages. In this review, we overview the outline of the mechanism of action as well as interrelation of the actions of these factors in controlling osteoblast differentiation, with special reference to the role of interleukin-11 in these processes.

The skeletal and the hematopoietic systems are two different research lines being united through the definition of a new function of bone-forming-osteoblasts, as a regulatory niche for hematopoietic stem cells (HSCs) . Many molecular pathways reveal the interaction between the HSC and osteoblast contributory to the maintenance of HSC number and function. Factors that regulate osteoblastic niche from surrounding tissues are also known, such as sympathetic nervous system, macrophages, and osteocytes. Furthermore, recent study has revealed that the skeletal system regulates remote hematopoietic organ as well. The bone acts as a central regulator of multiple organs.

Various kinds of cell types, such as osteoclasts, osteoblasts, hematopoietic cells, and mesenchymal cells, have been reported to exist in the bone marrow and communicate with each other. Although there have been many previous studies about bone marrow microenvironment, most of them were analyzed by conventional methods such as histological analysis and flow cytometry. These methods could not observe the dynamic cell movement in living bone marrow. Recently rapid development of fluorescent imaging techniques enables us to understand the cellular dynamics in vivo . That's why we have originally established an advanced imaging system for visualizing living bone tissues with intravital two-photon microscopy. Here we show the latest data and the detailed methodology of intravital imaging of bone marrow microenvironment, and also discuss its further application.

Adult hematopoietic stem cells (HSCs) are maintained in the bone marrow and give rise to all blood cell types. The maintenance and the differentiation of blood cells including immune cells are essential for host defense and oxygen delivery. HSCs are maintained in microenvironments called stem cell niches, which consists of various cell types in bone marrow. Recently, new visualization technologies and assay systems brought advances in studies on the stem cell niche. In addition, several reports demonstrated that osteoblasts and osteocytes regulate not only HSC homeostasis but also immune cell differentiation, suggesting a close relationship between bone cells and HSCs.

Haematopoietic stem cells (HSCs) are maintained in a specialized microenvironment termed "niche" in bone marrow (BM) cavities. Osteoclasts are required for formation of BM cavities, and thus, osteoclast-less animals exhibit BM cavity-less osteopetrotic phenotypes. Osteoclasts were also reportedly required for mobilization of haematopoietic stem and progenitor cells (HSPCs) to the periphery from BM cavities, however, how HSCs are maintained and HSPC mobilization is regulated in osteoclast-less animals were largely unknown. In this review, roles of osteoclasts in HSC maintenance and HSPC mobilization are discussed.

In bone marrow, the special microenvironments known as niches control proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs) . However, the identity and functions of the niches has been a subject of longstanding debate. Although it has been reported previously that osteoblasts lining the bone surface act as HSC niches, their precise role in HSC maintenance remains unclear. On the other hand, the adipo-osteogenic progenitors with long processes, termed CXCL12-abundant reticular (CAR) cells, which preferentially express the chemokine CXCL12, stem cell factor (SCF) , leptin receptor and PDGF receptor-β were identified in the bone marrow. Recent studies revealed that endothelial cells of bone marrow vascular sinuses and CAR cells provided niches for HSCs. The identity and functions of various other candidate HSC niche cells, including nestin-expressing cells and Schwann cells would also be discussed in this review.

Chondrocytes are derived from mesenchymal stem cells and play an essential role in endochondral ossification. Transcription factors, Sox9, Runx2, Runx3 and Osterix are critical for endochondral ossification, and regulate differentiation of mesenchymal stem cells into chondrocytes, and proliferation, maturation and apoptosis of chondrocytes. Recent advances in gene cloning approaches utilizing microarray and high-throughput sequencing technologies have revealed functional regulatory mechanisms of these transcription factors and contributed to understanding of molecular mechanisms of complex and harmonious chondrocyte differentiation.

Osteoblasts and osteocytes originate from pluripotent mesenchymal stem cells. Mesenchymal stem cells commit to osteogenic lineage and differentiate into mature osteoblasts and osteocytes through osteoprogenitor cells and preosteoblasts in response to multiple stimuli. The osteoblast commitment, differentiation, and functions are governed by several transcription factors. Among these transcription factors, runt-related transcription factor 2 (Runx2) is a crucial factor in osteoblast differentiation and controls bone formation. Differentiation toward these osteogenic lineage is controlled by a multitude of cytokines including WNTs, bone morphogenetic protein (BMP) , transforming growth factor-β (TGF-β) , hedgehog, parathyroid hormone (PTH) /parathyroid hormone related protein (PTHrP) , insulin-like growth factor-1 (IGF-1) , fibroblast growth factor (FGF) , and Notch. Although regulation of Runx2 activity is a point of convergence of many of the signal transduction routes, there is also a high degree of cross-talk between these pathways. Thus, the combined action of the signal transduction pathways induced by some cytokines determines the commitment and differentiation of mesenchymal stem cells toward the osteogenic lineage.

Mononuclear myeloid lineage cells, which are attracted to bone surfaces by chemokines and other factors, differentiate into multinucleated bone resorbing osteoclasts by cell fusion. Receptor activator of nuclear factor-κB ligand (RANKL) , which is expressed in mesenchymal cells, including osteocytes and hypertrophic chondrocytes, is essential for osteoclast differentiation and function. Osteoclasts have the capacity to resorb bone and impaired osteoclast differentiation and/or function leads to osteopetrosis, a rare disease in which mineralized bone cannot be removed. In contrast, excessive osteoclastogenesis causes diseases such as osteoporosis. Recent findings suggest that osteoclasts can also function as positive and negative regulators of osteoblastic bone formation. Thus, understanding of the molecular mechanisms that regulate osteoclastogenesis is important to develop therapeutic approaches to prevent bone diseases. This paper reviews recent findings of the molecular mechanisms regulating osteoclast differentiation and function.

Bone micro-environment appears to reflect bone turnover, i.e., frequency of bone remodeling. There are many bone-synthesizing mature osteoblasts, bone-resorbing osteoclasts, and a thick cell layer of preosteoblasts overlying mature osteoblasts in the region which shows active bone remodeling. Bone lining cells, - flattened, resting form of osteoblasts cover the quiescent bone surface, in which, however, osteocyte-lacunar canalicular system tend to be geometrically well-arranged. Thus, bone micro-environment seems to be regulated by preosteoblasts, bone marrow stromal cells and vascular endothelial cells, as well as osteoblasts and osteoclasts. But, precious biological function of preosteoblasts and bone marrow stromal cells are still under the investigation, e.g., due to many phenotypes of preosteoblasts. In this review, we will introduce histological and ultrastructural aspects on cellular involvement in bone micro-environment.

Cancer stem cells (CSCs) represent a subpopulation of tumour cells endowed with self-renewal and multi-lineage differentiation capacity. Clinically, drug resistance is the most important feature, because CSCs resist conventional cancer therapies and are involved in relapse. Therefore, major clinical challenges towards the complete eradication of minimal residual cancer are likely to target CSCs. Several molecules have been investigated as a target: specific signal transduction, cell surface marker, and microenviromental factors. Several drugs (salinomycin, metformin) have been also identified by chemical screening. For clinical use, however, more precise molecular mechanisms remain to be clarified.

We report a 40-year-old woman diagnosed as having acute myeloid leukemia with CBFB-MYH11. Before and after stem cell transplantation in the phase of molecular remission of the marrow, CBFB-MYH11-positive cells were detected by RT-PCR analysis in skin lesions. The former was pathologically diagnosed as leukemic infiltration, while the latter was considered to be graft-versus-host disease. We can speculate that a low level of leukemic stem cells not detectable by RT-PCR analysis remained in the bone marrow, at least prior to transplantation. This case may suggest interesting biological features of inv(16)-type acute myeloid leukemia.