PDF(Pubmed)
Abstract：
Human hematopoietic stem cell (HSC)-transferred humanized mice are valuable models for exploring human hematology and immunology. However, sufficient recapitulation of human hematopoiesis in mice requires large quantities of enriched human CD34+ HSCs and total-body irradiation for adequate engraftment. Recently, we generated a NOG mouse strain with a point mutation in the c-kit tyrosine kinase domain (W41 mutant; NOGW mice). In this study, we examined the ability of NOGW mice to reconstitute human hematopoietic cells. Irradiated NOGW mice exhibited high engraftment levels of human CD45+ cells in the peripheral blood, even when only 5,000-10,000 CD34+ HSCs were transferred. Efficient engraftment of human CD45+ cells was also observed in non-irradiated NOGW mice transferred with 20,000-40,000 HSCs. The bone marrow (BM) of NOGW mice exhibited significantly more engrafted human HSCs or progenitor cells (CD34+CD38- or CD34+CD38+ cells) than the BM of NOG mice. Furthermore, we generated a human cytokine (interleukin-3 and granulocyte-macrophage colony-stimulating factor) transgenic NOG-W41 (NOGW-EXL) mouse to achieve multilineage reconstitution with sufficient engraftment of human hematopoietic cells. Non-irradiated NOGW-EXL mice showed significantly higher engraftment levels of human CD45+ and myeloid lineage cells, particularly granulocytes and platelets/megakaryocytes, than non-irradiated NOGW or irradiated NOG-EXL mice after human CD34+ cell transplantation. Serial BM transplantation experiments revealed that NOGW mice exhibited the highest potential for long-term HSC compared with other strains. Consequently, c-kit mutant NOGW-EXL humanized mice represent an advanced model for HSC-transferred humanized mice and hold promise for widespread applications owing to their high versatility.
摘要：
人类造血干细胞（HSC）转移的人源化小鼠是探索人类血液学和免疫学的有价值的模型。然而,在小鼠中充分重述人造血需要大量富集的人CD34+HSC和全身照射才能充分植入。最近,我们产生了在c-kit酪氨酸激酶结构域具有点突变的NOG小鼠品系(W41突变体;NOGW小鼠).在这项研究中,我们检查了NOGW小鼠重建人类造血细胞的能力。受辐照的NOGW小鼠在外周血中显示出较高的人CD45细胞植入水平，即使仅转移了5,000-10,000个CD34HSC。在用20,000-40,000个HSC转移的未照射的NOGW小鼠中也观察到人CD45+细胞的有效移植。与NOG小鼠的BM相比，NOGW小鼠的骨髓（BM）显示出明显更多的移植人HSC或祖细胞（CD34CD38-或CD34CD38-细胞）。此外，我们产生了人细胞因子(白细胞介素-3和粒细胞-巨噬细胞集落刺激因子)转基因NOG-W41(NOGW-EXL)小鼠,以实现人造血细胞充分植入的多谱系重建.未照射的NOGW-EXL小鼠显示出较高的人CD45+和髓系细胞移植水平，特别是粒细胞和血小板/巨核细胞，人CD34+细胞移植后，未照射的NOGW或照射的NOG-EXL小鼠。系列BM移植实验表明，与其他品系相比，NOGW小鼠表现出最高的长期HSC潜力。因此,c-kit突变体NOGW-EXL人源化小鼠代表了HSC转移的人源化小鼠的先进模型，并且由于其高通用性而有望广泛应用。
