Karlsson Göran, Blank Ulrika, Moody Jennifer L, Ehinger Mats, Singbrant Sofie, Deng Chu-Xia, Karlsson Stefan
Department of Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University Hospital and Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, 22184 Lund, Sweden.
J Exp Med. 2007 Mar 19;204(3):467-74. doi: 10.1084/jem.20060465. Epub 2007 Mar 12.
Members of the transforming growth factor beta (TGF-beta) superfamily of growth factors have been shown to regulate the in vitro proliferation and maintenance of hematopoietic stem cells (HSCs). Working at a common level of convergence for all TGF-beta superfamily signals, Smad4 is key in orchestrating these effects. The role of Smad4 in HSC function has remained elusive because of the early embryonic lethality of the conventional knockout. We clarify its role by using an inducible model of Smad4 deletion coupled with transplantation experiments. Remarkably, systemic induction of Smad4 deletion through activation of MxCre was incompatible with survival 4 wk after induction because of anemia and histopathological changes in the colonic mucosa. Isolation of Smad4 deletion to the hematopoietic system via several transplantation approaches demonstrated a role for Smad4 in the maintenance of HSC self-renewal and reconstituting capacity, leaving homing potential, viability, and differentiation intact. Furthermore, the observed down-regulation of notch1 and c-myc in Smad4(-/-) primitive cells places Smad4 within a network of genes involved in the regulation HSC renewal.
转化生长因子β（TGF-β）超家族的生长因子成员已被证明可调节造血干细胞（HSC）的体外增殖和维持。作为所有TGF-β超家族信号的共同汇聚水平，Smad4在协调这些效应中起关键作用。由于传统基因敲除导致胚胎早期致死，Smad4在HSC功能中的作用一直难以捉摸。我们通过使用Smad4缺失的诱导模型并结合移植实验来阐明其作用。值得注意的是，由于贫血和结肠黏膜组织病理学变化，通过激活MxCre系统诱导Smad4缺失与诱导后4周的存活不相容。通过几种移植方法将Smad4缺失隔离到造血系统，证明Smad4在维持HSC自我更新和重建能力方面发挥作用，同时保留归巢潜力、活力和分化能力。此外，在Smad4（-/-）原始细胞中观察到的Notch1和c-myc的下调将Smad4置于参与调节HSC更新的基因网络中。
