Analysis of intramedullary extramedullary B lymphopoiesis

使用三个骨髓形成减少的骨化突变小鼠品系，我们发现它们的B细胞生成缺乏基本的骨髓腔。系统发育观察支持我们的发现，提示破骨细胞与B淋巴细胞生成之间存在联系。为了弄清这个问题，本研究进行了如下研究：1)在骨髓B淋巴细胞的生成中，WNT-3a作用于基质细胞，导致B淋巴细胞的生成受到抑制。然而，该因子并不影响破骨细胞的形成。2)众所周知，Notch信号会抑制B淋巴细胞的生成。我们使用重组配体Delta-1评估了Notch信号在破骨细胞形成中的作用。Notch信号通过抑制破骨细胞前体和支持破骨细胞发育的基质细胞来抑制破骨细胞的形成。3)针对Toll样受体和肿瘤坏死因子-α的配体的反应性，我们证明了不同的破骨细胞前体存在于每个组织中，包括骨髓、脾、腹膜和胎肝。4)我们建立了胚胎干细胞的培养体系，以诱导ES细胞向破骨细胞、内皮细胞和成骨细胞分化。现在，我们已经建立了一个体外研究骨髓形成的模型系统。我们已经发表了论文[1)、2)和4)，3)的手稿已经提交。最近，根据我们的建议，骨髓中调控B淋巴细胞生成的候选基因被报道。我们很快就会弄清楚B淋巴细胞的生成机制。

Using three osteopetrotic mutant mouse strains, which carry reducing bone marrow formation, we have found their B lumphopoiesis lacks in rudimentary bone marrow cavities. The phylogenetical observation supports our finding, suggesting the presence of the relation between osteoclasts and B lymphopoiesis. To be clear the question, this study was performed.The results are shown as follows:1) In bone marrow B lymphopoiesis, Wnt-3a acts stromal cells, resulting in suppressing B lymphopoiesis. However, the factor does not affect osteoclastogenesis.2) Notch signaling is known to inhibit B lymphopoiesis. We assessed the effect of Notch signaling on osteoclastogenesis by using a recombinant ligand, Delta-1. The Notch signaling suppresses osteoclastogenesis directed to osteoclast precursors and through stromal cells, which support osteoclast development.3) Indicating the responsiveness to ligands for toll-like receptors and tumor necrosis factor-α, we demonstrated the presence of distinct osteoclast precursors maintained in each tissue including bone marrow, spleen, peritoneal cavity, and fetal liver.4) We developed the culture system of embryonic stem cells to induce the differentiation of ES cells to osteoclasts, endothelial cells, and osteobasts.Now, we have a model system to study in vitro bone marrow formation.We have already published the papers [1),2),and4)], and the manuscript for 3) has been submitted. Recently, based on our propose, candidate genes for regulating B lymphopoiesis in bone marrow are reported. We will make clear the mechanism of B lymphopoiesis, soon.