Erythropoiesis has classically been described as occurring in two waves: first primitive and then definitive erythropoiesis. In the mouse embryo, definitive erythropoiesis begins in the yolk sac and then shifts to the liver, spleen, and bone marrow. The fetal liver serves as the primary organ for erythroid cell expansion and maturation at mid-gestation and its mechanisms have been well investigated with special attention to niche cells expressing cytokines such as SCF, TPO and IGF2. Previously, our group reported that DLK1(+) hepatoblasts support fetal liver hematopoiesis, particularly erythropoiesis, through EPO, SCF and matrix secretion. Loss of DLK1(+) hepatoblasts in Map2k4(-/-) mouse embryos resulted in decreased numbers of hematopoietic cells in the fetal liver. When sorted DLK1(+) hepatoblasts were further analyzed by microarray, several genes encoding proteinases and peptidases were highly expressed in DLK1(+) hepatoblasts. Based on the hypothesis that high molecular weight proteins are digested into small peptides that may regulate hematopoiesis, we screened out peptides, and identified KS-13 (PCT/JP2010/067011). Both KS-13 and modified KS-13, known as SL-13R, proliferate and increase the number of hematopoietic stem/progenitors from human cord blood cells in vitro. We hereby present our findings on the extrinsic regulation of embryonic erythropoiesis with special attention to niche cells, identification of niche-derived peptides, and implications for future hematotherapy.

The TET2 gene is an epigenetic regulator. Loss-of-function mutations of TET2 are found in a variety of blood cancers in both myeloid and lymphoid lineages. Meanwhile, clonal blood cells carrying leukemia-driver mutations have been detected in significant proportions of different cohorts without blood cancers. Amongst these driver mutations, those in the TET2 gene are second/third most frequent. The presence of such clonal blood cells predicts elevated risk for developing various blood cancers. These results indicate that acquisition of TET2 mutations in blood cells does not per se cause cancers; however, TET2 mutations are likely to be acquired at the common myeloid/lymphoid progenitor levels. Such hematopoietic stem/progenitor cells may wait for second hit mutations for the development of multiple blood cancers, and play a role as pre-leukemia/pre-lymphoma cells. Combinations of TET2 and disease-specific gene mutations have been demonstrated in individual blood cancers. Correspondingly, mice into which such combinatorial gene abnormalities have been introduced will recapitulate the respective blood cancers.

We report a case of slowly progressive anti-Yo-associated paraneoplastic cerebellar degeneration (PCD) with breast cancer in a 54-year-old woman. The symptoms of limb and truncal ataxia, and dysarthria gradually progressed during the course of 1 year, and the modified Rankin scale (mRS) score was 2. A mastectomy with sentinel lymph node resection was performed for the breast cancer. No malignant cells were found on histopathological examination of the lymph node. Combination chemotherapy with adriamycin and cyclophosphamide (AC) prevented neurologic deterioration. However, subsequent treatment with trastuzumab and paclitaxel did not prevent progression of the symptoms (mRS score 3). Brain magnetic resonance imaging showed atrophy of the cerebellar hemispheres without brain stem atrophy. Anti-Yo antibody was detected in the serum, which led to a diagnosis of anti-Yo-associated PCD. We resected an enlarged axillary lymph node, which was found on computed tomography. The histopathological analysis of the lymph node revealed foreign body granuloma, which suggested an association with necrotic malignant tissue. Following additional tegafur-uracil therapy and two courses of intravenous immunoglobulin (IVIg), the cerebellar signs and symptoms gradually improved (mRS score 2). The clinical course shows that PCD can present as a slowly progressive cerebellar symptom. We propose an active treatment for anti-Yo-associated PCD consisting of tumor resection, combined chemotherapy, and IVIg.

Periodontitis remains highly prevalent all over the world and can lead to loss of the affected teeth. Thus, establishing a brand-new treatment that enables the regeneration and rebuilding of periodontal tissue destroyed by periodontitis represents a task of tremendous importance. Our pre-clinical studies and clinical trials suggested that efficacy is expected from basic fibroblast growth factor(FGF-2)in stimulating regeneration of periodontal tissue. Development of the osteoconductive carrier for FGF-2 drug will further extend the indications in the field of dental medicine.

Cell replacement therapy is attractive as a novel strategy for stroke patients. To realize this therapy, safer and more effective cell resources are now required. Since both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can retain high replication competence and pluripotency when they differentiate into various kinds of cells, they are regarded as a promising cell source for cell replacement therapy. Recent progress includes the combination of novel transcriptional factors that can convert somatic cells to various kinds of mature neuronal cells and neural stem cells without requiring embryonic stem fate. In this paper, we would like to discuss the advantage, issues, and possibility of clinical application of these cells for cell replacement therapy for post-stroke patient.

It is now well recognized that new neurons are continuously generated in the specific regions of the adult brain across all mammalian species including humans. Now the cumulative findings demonstrate that this capacity for neurogenesis at the adult stage is associated with self-repair mechanisms in the damaged brain. Then, one of the main reasons that in vivo growth factor treatment is worth studying is the expectation that such treatment would promote the regeneration of neurons after stroke. Here we show the cumulative evidence that this approach is feasible as one of the brain repair therapies.

We conduct a double-blind randomized placebo-controlled clinical trial (Phase III: confirmatory trial) of intravenous infusion of autologous mesenchymal stem cells for cerebral infarction patients. The objectives of this study were to examine feasibility, safety, and efficacy of cell therapy using auto serum-expanded autologous mesenchymal stem cells derived from bone marrow in the stroke patients. Inclusion criteria is (1) Cerebral infarction onset within 40 days, (2) Supra-tentorial cerebral infarction(NINDS-III 1990) diagnosed by MRI(or CT), MRA (3D-CTA or DSA), ECG, chest X-ray etc., (3) Classified under grade 4 or 5 of mRS (modified Rankin scale), (4) Age between 20 to 80, (5) The written informed consent from subjects and legal representative is provided.