Onai Nobuyuki, Obata-Onai Aya, Schmid Michael A, Manz Markus G
Institute for Research in Biomedicine (IRB), Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland.
Ann N Y Acad Sci. 2007 Jun;1106:253-61. doi: 10.1196/annals.1392.015. Epub 2007 Mar 14.
Flt3-ligand is a nonredundant cytokine in type I interferon-producing cell (IPC) and dendritic cell (DC) development. We demonstrated that IPC and DC differentiation potential is confined to Flt3(+)-hematopoietic progenitor cells, that Flt3-ligand drives development along both lymphoid and myeloid developmental pathways from Flt3(+)-progenitors to Flt3(+)-IPCs and -DCs, and that in vivo pharmacologic inhibition of Flt3-signaling leads to disruption of IPC and DC development in spite of consecutive Flt3-ligand upregulation in treated animals. We here summarize our recent findings that overexpression of human Flt3 in Flt3(-) and Flt3(+) hematopoietic progenitors rescues and enhances their IPC and DC differentiation potential, respectively. Based on these data, we propose an instructive, demand-regulated, cytokine-driven IPC and DC regeneration model, where high Flt3-ligand levels initiate a self-sustaining, Flt3-STAT3 and -PU.1-mediated IPC and DC differentiation program in Flt3(+)-hematopoietic progenitor cells.
Flt3配体是I型干扰素产生细胞（IPC）和树突状细胞（DC）发育过程中一种不可或缺的细胞因子。我们证明，IPC和DC的分化潜能局限于Flt3(+)造血祖细胞，Flt3配体驱动从Flt3(+)祖细胞到Flt3(+)IPC和DC的淋巴样和髓样发育途径的发育，并且在体内，尽管经处理的动物中Flt3配体持续上调，但Flt3信号的药理抑制仍会导致IPC和DC发育的破坏。我们在此总结我们最近的发现，即Flt3(-)和Flt3(+)造血祖细胞中人类Flt3的过表达分别挽救并增强了它们的IPC和DC分化潜能。基于这些数据，我们提出了一种指导性的、需求调节的、细胞因子驱动的IPC和DC再生模型，其中高Flt3配体水平在Flt3(+)造血祖细胞中启动一个自我维持的、Flt3-STAT3和-PU.1介导的IPC和DC分化程序。
