Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2378-83. doi: 10.1073/pnas.1019524108. Epub 2011 Jan 24.
Hematopoietic stem cells (HSCs) both self-renew and give rise to all blood cells for the lifetime of an individual. Xenogeneic mouse models are broadly used to study human hematopoietic stem and progenitor cell biology in vivo. However, maintenance, differentiation, and function of human hematopoietic cells are suboptimal in these hosts. Thrombopoietin (TPO) has been demonstrated as a crucial cytokine supporting maintenance and self-renewal of HSCs. We generated RAG2(-/-)γ(c)(-/-) mice in which we replaced the gene encoding mouse TPO by its human homolog. Homozygous humanization of TPO led to increased levels of human engraftment in the bone marrow of the hosts, and multilineage differentiation of hematopoietic cells was improved, with an increased ratio of myelomonocytic verus lymphoid lineages. Moreover, maintenance of human stem and progenitor cells was improved, as demonstrated by serial transplantation. Therefore, RAG2(-/-)γ(c)(-/-) TPO-humanized mice represent a useful model to study human hematopoiesis in vivo.
造血干细胞（HSCs）既能自我更新，又能为个体的一生产生所有血细胞。异基因小鼠模型广泛用于研究体内人类造血干/祖细胞生物学。然而，在这些宿主中，人类造血细胞的维持、分化和功能并不理想。血小板生成素（TPO）已被证明是支持 HSCs 维持和自我更新的关键细胞因子。我们生成了 RAG2(-/-)γ(c)(-/-) 小鼠，在这些小鼠中，我们用人同源物替换了编码小鼠 TPO 的基因。TPO 的纯合人源化导致宿主骨髓中人类植入物水平增加，造血细胞的多谱系分化得到改善，骨髓单核细胞与淋巴谱系的比例增加。此外，正如连续移植所证明的那样，人类干/祖细胞的维持得到了改善。因此，RAG2(-/-)γ(c)(-/-) TPO 人源化小鼠代表了一种有用的模型，可用于研究体内人类造血。
