Hematology in Japan: past, present and future

In this article I hope to introduce you to the history of hematology in Japan. The field of hematology has a long history with a firm basis in Japan.

Here, we recently celebrated the 70th anniversary of the Japanese Society of Hematology. The JSH, which was established in 1937 in Kyoto, was the second hematology organization formed in the world. The French Society of Hematology, which was formed in 1927, was the first. ASH was formed 20 years after the JSH, in 1957.

In addition to the JSH, which has about 6,000 members, Japan is also home to the Japanese Society of Clinical Hematology, which was established in 1959 in Tokyo. Throughout its history the JSCH has made significant contributions to the progress of clinical hematology, and as of 2008, had 5,817 hematologist members. The two organizations merged in 2008 under the title of the Japanese Society of Hematology, forming one of the largest hematology associations in the world.

In addition to the JSH, there are two other hematology-related societies in Japan, the Japanese Society on Thrombosis and Hemostasis in Tokyo, established in 1978, and the Japanese Society for Lymphoreticular Tissue Research, founded in Nagoya in 1961.

The JSH-directed academic journal, Acta Haematologica Japonica was established in 1938 and is the fourth-oldest hematology journal. The first three journals created were Folia Haematologica (Germany, 1904), Hematologica (Italy, 1920) and La Sang (France, 1927).

Acta Haematologica Japonica was renamed the International Journal of Hematology in 1991, and currently has about 12,000 subscribers. Another official journal, Rinsho-Ketsueki — the Japanese Journal of Clinical Hematology, which is published in Japanese — was established at about the same time as Blood, which was started by ASH in 1957. With about 8,800 subscribers, the journal focuses on clinical hematology.

Achievements of hematopoiesis research in Japan

In the 70 years since the JSH was established, Japanese hematologists have contributed significantly to the vast progress of clinical hematology. It is impossible to introduce all the scientific and clinical accomplishments in the various fields of hematology made by Japanese hematologists in recent years within this editorial. Among the tremendous contributions, the most striking one has been the research done in the field of hematopoiesis.

Hematopoietic stem cells are cells with self-renewal and multilineage differentiation potentials, as defined by Till and McCulloch in 1961. Worldwide efforts, including work by Japanese hematologists, have been devoted to the identification and isolation of such cells. The importance of stem cell research has again recently been recognized as a cover story in the Feb. 9, 2009, issue of Time.

Over time, many Japanese investigators have contributed to this field. In 1977, Kitamura et al made the first important observation that mast cells are derived from hematopoietic stem cells shown by transplantation of bone marrow cells from mutant mice. Also in 1977, Miyake et al were the first to purify erythropoietin, and in 1986, granulocyte colony-stimulating factor was cloned independently in Japan.

In the field of immunology, interleukins (IL-2, IL-4, IL-5, and IL-6) were initially identified in Japan, as described in a review article published in the Philosophical Transactions of the Royal Society B. In addition, the receptors for several interleukins, including gp130, the common beta chain and the common gamma chain were identified between 1990 and 1992 by Japanese scientists.

One of the most renowned leaders in HSC research is Makio Ogawa, MD, PhD, who trained Tatsutoshi Nakahata, MD, Toshio Suda, MD, Yoshiaki Sonoda, MD, and many others. These investigators later became distinguished leaders in the field of hematopoiesis research in Japan. Fumimaro Takaku, MD, who contributed greatly to the establishment of hematopoiesis research in Japan along with many excellent coworkers, including Drs. Miura as a group leader, Suda in the field of HSCs, Nagata in the field of apoptosis, Asano in the field of G-CSF, Motoyoshi in the field of M-CSF, and others should also be mentioned.

Hiromitsu Nakauchi, MD, and his colleagues were the first to demonstrate that only one cell is sufficient to reconstitute the entire hematopoietic system of recipient mice for a long period, that a single HSC can self-renew and differentiate in all blood lineages, and that there is significant heterogeneity among HSCs. Nakahata et al recently contributed to the making of a protocol for efficient induction of blood cells from monkey embryonic stem cells.

As for the field of HSC chemotactic factors, stroma cell-derived factor-1 (SDF1, now designated CXCL12) was identified in PA6 cells by expression cloning by Nagasawa et al. They also reported that SDF1/CXCR4 signaling is essential for B cell development. During embryonic development fetal liver HSCs migrate into the spleen and the bone marrow in an SDF1-dependent manner. SDF1 appears to act as an attractant factor for HSCs, recruiting them back to their niches, and SDF1/CXCR4 signaling is believed to be important for angiogenesis, neurogenesis and the migration of primordial germ cells.

Transcriptional regulation is now known to be critical in HSC development. In this category, RUNX1 was identified in acute myeloid leukemia by Miyoski et al; Runx1 is essential for definitive hematopoiesis, being mainly required for megakaryocyte and lymphocyte differentiation as proven by Ichikawa et al.

As for the various hematopoietic progenitor populations lying between HSCs and mature cells, common lymphoid progenitors and myeloid progenitors have been identified by Japanese researchers. These progenitors are useful tools for clarifying the relationships among these populations in terms of differentiation pathways.

HSC research in the last few years

Stem cell research has recently received a big boost from excellent investigators in JSH, including Suda, Nakauchi, Nakahata, Koichi Akashi, MD, Toru Nakano, MD, Shinya Yamanaka, MD, and many others. Some of their outstanding accomplishments in the field of hematopoietic stem cell research are reviewed below.

Hematopoietic stem cells (HSCs) and their niches. In 1961, Till and McCulloch defined HSCs as a colony-forming unit in the spleen (CFU-S). The stem cell system of an adult tissue consists of stem cells and the adjoining cells in a given tissue. The interaction of HSCs with their microenvironment, known as the “stem cell niche,” is critical for adult hematopoiesis in the bone marrow.

The quiescent state (Go in the cell cycle) of HSCs is an essential biological mechanism for adult tissues to maintain a stem cell component in the undifferentiated state for a long period of time. Suda et al clarified that quiescent HSCs adhere to the hypoxic niche in the endosteal niche region of the bone marrow through the signaling of niche factors such as the receptor Tie 2/its ligand, Angiopoietin-I, mpl/ thrombopoietin or homotypic adhesion via N-cadherin. Therefore, the bone marrow niche regulates the number and rate of differentiation of HSCs, allowing HSCs to enter the cell cycle and proliferate to supply progenitors of committed hematopoietic cells and reinducing their quiescence.

In addition, it has been demonstrated that reactive oxygen species (ROS) induce the exit of HSCs from the niche through down-regulation of N-cadherin and up-regulation of MAPK p38, and INK4A in HSCs. These studies clearly indicate that HSCs reside at the endosteal niche, which is hypoxic and that low concentrations of ROS are required for maintaining the cell’s quiescence.

The concept of “cancer stem cells,” which also have the capacity for self-renewal, has been proposed. If leukemic stem cells are indeed present in the bone marrow niche and are hence maintained in a more quiescent state, it could explain the observed resistance to antileukemia drugs.

Cell lineage differentiation of HSCs by transcription and signaling. HSCs are cells with a capacity for self-renewal, and the ability to differentiate into all blood cells lineages. Research on the differentiation of HSCs into these different cell lineages has made major advances via the identification of transcription factors and signaling pathways that guide these processes. Akashi and his coworkers demonstrated that reciprocal activation of GATA-1 and PU.1 marks initial specification of HSCs into myelo-erythroid and myelo-lymphoid lineages. They demonstrated that, depending on their relative expression level, PU.1 and GATA-1 direct HSCs to one or the other committed precursor cells. That is, GATA-1 is responsive for the differentiation of HSCs to myeloid common precursors, and PU.1 for the differentiation to precursor cells of granulocytes, monocytes and lymphoid cells. They found that precursors of eosinophilic and basophilic lineages are present down-stream from granulocytic and monocytic precursors. They also demonstrated that such differentiation is directed by sequential competitive expression of the transcription factors GATA-2 and C/EBPalpha.

Mechanisms of self-renewal in HSCs. Nakauchi and his colleagues investigated various mechanisms of HSC self-renewal and reported that enhanced self-renewal of HSCs is mediated by the polycomb gene product Bmi-1. They also demonstrated that HSC “hibernation” is modulated by cytokine signals via lipid rafts mimicking niche signals, with TGF-beta being a candidate bone marrow niche signal. In addition, regarding thrombopoiesis, they demonstrated that the adaptor protein Lnk negatively regulates self-renewal of HSCs by modifying thrombopoietin-mediated signal transduction. They also succeeded in the generation of functional platelets from mouse and human embryonic stem cells in vitro via embryonic stem cell-sacs, VEGF-promoted structures that concentrate hematopoietic progenitors. This finding may make it possible to establish a safe, stable and blood donation-independent supply system of platelets in clinical medicine.

Future perspectives

Studies on HSCs in hematology seem to have provided a stimulus for studies of other stem cells by leading stem cell biology research in general. For example, recent observations on quiescent HSCs and their unique metabolism may elucidate the mechanism of aging and leukemogenesis.

It has recently been shown that induced pluripotent stem (iPS) cells are generated from adult human dermal fibroblasts by retrovirus-mediated introduction of four factors, Oct3/4, Sox2, c-Myc, and Klf4. These studies should promote basic research on dedifferentiation as well as pluripotent stem cells and may lead to possible clinical application as it relates to a number of disease mechanisms, in drug screening, in toxicology, and in regenerative medicine. These accomplishments in Japan are expected to continue and to increasingly contribute to the further development of this field.

Yoshihito Yawata, MD, PhD, is a Professor Emeritus (hematology) at Kawasaki Medical School and is a member of the HemOnc Today Editorial Board.
Dr. Yawata made the following acknowledgment: I greatly appreciate the scientific support, especially of Professor Toshio Suda (Keio University, Tokyo), one of my closest friends, and of other investigators, such as Professors Kouichi Akashi, Hiromitsu Nakauchi and Hideo Ema, who provided the newest information on hematopoiesis research.

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