Investigating the molecular mechanism of HIF in hypoxic stress

The top three causes of death in Japan are malignant tumor, ischemic heart disease, and cerebral vascular disease. A common cause of these diseases is low oxygen tension in our body, known as hypoxic stress. The key transcription factors that regulate response to hypoxic stress are the Hypoxia Inducible Factors (HIFs). There are 3 types of HIFs: HIF-1α are expressed ubiquitously, HIF-2α are mainly expressed in endothelial cells, and HIF-3α works as an inhibitor against HIF-1α and HIF-2α.

In our laboratory, we investigate the molecular mechanisms of HIFs for hypoxic responses in vivo. We investigate the roles of HIF-2α for tumor vascularization, erythropoiesis, retinopathy of prematurity using HIF-2α knockdown mice. We also analyze the roles of HIF-3α for pulmonary hypertension and lung development using HIF-3α knockout mice. We try to clarify the diversity of HIF functions in response to various hypoxic stimuli.

Analysis of functional adult stem cells and progenitor cells for clinical application

Adult stem cells are undifferentiated cells, found in  adult tissues, which have stem cell characteristics such as self-renewal and differentiation potency. Since the use of embryonic stem cells is controversial, researchers are now investigating adult stem cells as a source of cells for application in regenerative medicine, the goal of which is to replace the dysfunctional cells in the tissue or support in the recovery of local cells. However, the self-renewal, proliferation, and other properties of the various adult stem cells are different so it is necessary to properly analyze their characteristics and their potency before applying adult stem cells in clinical treatment for specific disease.

In our laboratory, we are focusing on  the analysis of the biological characteristics and functions of mesenchymal stem cells and endothelial progenitor cells from several sources for application in future clinical treatments. Furthermore, we are aiming to clarify the underlying mechanisms regulating mesenchymal stem cells and endothelial progenitor cells in order to support tissue or organ recovery.

Researching cancer relapse with cancer stem cells

To cure cancer, it is necessary to prevent relapse and metastasis. In recent years,  research has been focused on a sub-population of cancer cells, so called cancer stem cells, which contribute to the relapse of cancer.

Together with the Deptartment of Breast-Thyroid- Endocrine Surgery Group at the Univ. of Tsukuba, our lab is researching the characteristics of cancer stem cells and the effect of hypoxia and the microenvironment of breast tissue on cancer stem cells using breast cancer cell lines and established cells line derived from breast tumor tissues and pleural effusion.

Decoding ectodermal development using an ES cell approach

ES cells are pluripotent stem cells meaning they can differentiate into any of the cell types derived from the three germ layers. Therefore, it is expected that ES cells will be used as a cell source for regenerative medicine. In addition, ES cells are a useful tool to study mammalian development in vitro.

Using an ES cell based approach, it has now become possible to recapitulate most of the early developmental events in vitro. During early development, the cells in our body are generated from three germ layers known as ectoderm, mesoderm and endoderm. Among the three germ layers, we are particularly interested in ectodermal differentiation. Ectoderm eventually generates neural tissue (CNS, neural crest, sensory placode) and epidermis.

How is the cell-fate of each ectodermal subpopulation determined during early development in mammals? We are trying to answer this question using a number of ES cell based approaches.