Although cancer is a genetic disease, epigenetic alterations are involved in its initiation and progression. Previous studies showed that the introduction of endogenous small-sized, noncoding ribonucleotides including microRNA200c, -302s, and -369 resulted in the induction of cellular reprogramming. MicroRNA200c inhibits the epithelial-mesenchymal transition. MicroRNA302s induces the demethylation of the tumor suppressor gene promoter region, while microRNA369 changes cancer cell metabolism. These three types of microRNA induce cancer cellular reprogramming and modulate malignant phenotypes of human cancer cells. These results suggest that the appropriate delivery of functional small-sized ribonucleotides may be a novel approach to the treatment of human cancer.

Biomarkers are defined as characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers obtained by PCR or flow cytometry are used for the diagnosis and subtyping of hematopoietic tumor cases. They are also used to predict the effectiveness of molecular-targeted therapies and detect minimal residual leukemia cells. In order to cure leukemia, it is necessary to eradicate leukemia stem cells. For that purpose, biomarkers to identify and characterize the leukemia stem cells in each case are needed. Therefore, we examined molecules involved in various stemness-related signaling pathways, especially NOTCH signaling in acute leukemia cells. In T-lymphoblastic leukemia cells, which often have activating NOTCH1 mutations, NOTCH works in oncogenic signaling. Although acute myeloid leukemia (AML) cells express NOTCH and NOTCH ligands, it is still controversial whether NOTCH is oncogenic or tumor-suppressive. To utilize the expression and activation of NOTCH as a leukemia stem cell biomarker, further investigation is required. Other stemness-related signaling molecules such as WNT, HEDGEHOG, HIF, and mTOR are also under investigation to assess whether they can be used as stem cell biomarkers in a clinical setting.

A 24-year-old woman was hospitalized with seizures in 2002. Magnetic resonance imaging demonstrated an intraspinal mass and inhomogeneous gadolinium enhancement along the cerebrospinal meninges. Cerebrospinal fluid (CSF) cytology showed large atypical cells expressing CD2, cytoplasmic CD3, CD7, CD13 and CD30. The patient was finally diagnosed with primary central nervous system anaplastic large cell lymphoma (ALCL). She completed 5 courses of methotrexate (MTX)/ procarbazine (PCZ)/ vincristine (VCR) (MPV) chemotherapy, followed by 2 courses of high dose cytarabine (AraC) and achieved a complete remission. In 2003, she suffered from headache. CSF analysis showed atypical lymphoid cells expressing CD 30. First CNS relapse was diagnosed. She then underwent autologous peripheral blood stem cell transplantation (auto-PBSCT) after administration of thiotepa, buslfan, and cyclophosphamide. However, second CNS relapse occurred in 2004. She received 5 courses of MPV chemotherapy followed by 36 Gy of craniospinal irradiation. Although there was no recurrence of the CNS disease, a third relapse was detected in the right breast in 2009. Pathological and immunohistochemistry analysis revealed ALK-1 positive ALCL. She was treated with 6 courses of cyclophosphamide/adriamycin/vincristine/predonine (CHOP) chemotherapy and 30.6 Gy of local radiation therapy. She has remained in remission for 6 years, to date, since the last therapy and has an excellent quality of life.

Hematopoietic stem cells (HSCs) are predominantly in a quiescent state, thereby avoiding depletion due to various stresses. However, quiescent HSCs are vulnerable to mutagenesis due to low-fidelity DNA repair. The mechanism by which HSCs avoid mutation accumulation remains to be elucidated. HSCs are normally resistant to apoptosis because of their abundant expressions of pro-survival Bcl-2 family genes. In contrast, p53 is activated in HSCs in response to DNA damage. We have recently shown that pro-apoptotic Bcl-2 signals are activated through p53 preferentially in HSCs with damaged DNA. Aspp1, an apoptosis-stimulating protein of p53, is highly expressed in HSCs and coordinates with p53 to maintain the genomic soundness of the HSC pool. In this review, we will summarize apoptosis regulation and the roles of p53 in HSCs, and introduce our findings showing coordinated regulations of HSC self-renewal, DNA damage tolerance and hematological malignancies by Aspp1 and p53.

The lacrimal gland has an essential role in maintaining a homeostatic environment for a healthy ocular surface by tear secretion. Dry-eye disease, caused by lacrimal gland dysfunction, is a prevalent eye disease that results in corneal epithelial damage. Regenerative medicine, such as stem cell therapy, is expected to be a promising approach to restore the lacrimal gland function. Recently, a novel strategy has been reported of developing a fully functioning bioengineered organ by engraftment of a bioengineered organ germ generated via 3-dimensional cell manipulation using immature stem cells in vitro. We demonstrated an orthotopic transplantation of the bioengineered lacrimal gland germ into adult mice, in which the extra-orbital lacrimal gland has been removed. This mouse model mimics the corneal epithelial damage caused by lacrimal gland dysfunction. The bioengineered lacrimal gland germ and harderian gland germ both developed in vivo; they achieved physiological functionality, including tear secretion in response to nervous stimulation and ocular surface protection. This study provided novel evidence for the successful replacement of a fully functional lacrimal gland via engraftment of a bioengineered germ.

Under physiological and pathological conditions, complex cellular interplays take place in living animals. However, the conventional microscope using two-dimensional analysis is not sufficient for analyzing cell dynamics and functions in vivo. Thus, we improved the in vivo imaging technique based on multi-photon microscopy, and we then identified single platelet behaviors in the developing thrombus. We utilized XYZT high-speed imaging, which visualized platelet fate in vivo. This novel technique is anticipated to provide new insights into physiological and pathological conditions involving platelets.

Recent genome studies have identified recurrent somatic mutations in various myeloid malignancies, including acute myeloid leukemia, myelodysplastic syndrome and myeloproliferative neoplasm. These mutations frequently occur in epigenetic regulator genes, and functions of the proteins encoded by these genes in hematopoietic cells have been extensively analyzed, as reported recently. It is noteworthy that several epigenetic regulator genes, such as DNMT3A, TET2 and ASXL1, have also been identified in pre-leukemic stem cells. As targeting pre-leukemic stem cells would be a promising therapeutic approach, further investigations of epigenetic abnormalities in hematopoietic cells are anticipated to lead to the development of novel epigenetic therapies. In this review, we discuss recent genetic and functional data regarding epigenetic regulator genes and the future landscape of this new research field.

The functional cells or tissues derived from human induced pluripotent stem cells (iPSCs) make it possible to overcome with the insufficiency of cell sources for regenerative medicine, to investigate the precise mechanism of human organogenesis and disease, and to develop the new drugs. Especially for type 1 diabetes, making mature pancreatic beta cells from human iPSCs might have a good opportunity of regenerative medicine. However, so far in vitro, producing the fully maturated pancreatic beta cells is not achieved. Here we review the previous reports and discuss the possibility and validity of our strategy for making mature pancreatic beta cell with three-dimensional culture of pancreatic organoid derived from human iPSCs.

Persistent inflammation in rheumatoid arthritis (RA) can lead to the profound degradation and defect of articular cartilage. We can treat or induce the regeneration for the partial cartilage defect using the autologous chondrocytes implantation (ACI) or the matrix-assisted ACI. However, these regenerative methods cannot be applicable for the large size defect due to their limitation of the formable size or available cell numbers. The cell sheet technology or the intra-articular injection technique using the mesenchymal stem cells or the induced pluripotent stem cells (iPS cells) could be applied for the large size cartilage defect in RA patients in the future after additional studies.