A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development

Abstract

Notch1 is known to play a critical role in regulating fates in numerous cell types, including those of the hematopoietic lineage. Multiple defects exhibited by Notch1-deficient embryos confound the determination of Notch1 function in early hematopoietic development in vivo. To overcome this limitation, we examined the developmental potential of Notch1–/– embryonic stem (ES) cells by in vitro differentiation and by in vivo chimera analysis. Notch1 was found to affect primitive erythropoiesis differentially during ES cell differentiation and in vivo, and this result reflected an important difference in the regulation of Notch1 expression during ES cell differentiation relative to the developing mouse embryo. Notch1 was dispensable for the onset of definitive hematopoiesis both in vitro and in vivo in that Notch1–/– definitive progenitors could be detected in differentiating ES cells as well as in the yolk sac and early fetal liver of chimeric mice. Despite the fact that Notch1–/– cells can give rise to multiple types of definitive progenitors in early development, Notch1–/– cells failed to contribute to long-term definitive hematopoiesis past the early fetal liver stage in the context of a wild-type environment in chimeric mice. Thus, Notch1 is required, in a cell-autonomous manner, for the establishment of long-term, definitive hematopoietic stem cells (HSCs).

The microenvironment of the embryonic neural stem cell: Lessons from adult niches?

“…In turn, notch activation in the hematopoietic stem cells was increased, leading to an increase in the stem cell numbers (Calvi et al, 2003). This notch dependence of hematopoietic stem cells is also seen in development as the notch 1-null (Kumano et al, 2003), notch 1-chimeric (Hadland et al, 2004), and RBPjkappa (a transcription factor required for notch activity)-null mice (Robert-Moreno et al, 2005) all show abnormal hematopoietic stem cell development. In muscle stem cells (satellite cells), activated notch increases proliferation while inhibition of notch signaling by its antagonist, numb, results in commitment of progenitor cells to myoblast cell fate (Conboy and Rando, 2002).…”

“…Soluble factors such as BMPs (Xie and Spradling, 1998;Kobielak et al, 2003;Zhang et al, 2003;Andl et al, 2004;He et al, 2004;Yamashita et al, 2005), FGFs (Kashiwakura and Takahashi, 2005), Shh (Madison et al, 2005;Crosnier et al, 2006), and Wnts (Gat et al, 1998;Korinek et al, 1998;Huelsken et al, 2001;Niemann et al, 2002;Reya et al, 2003;Willert et al, 2003) are present within the niche and can originate from support cells, stem cells themselves, or differentiated cell. Cell-to-cell contact-mediated signaling is also present in adult niches in the form of connexins (Juneja et al, 1999;Plum et al, 2000), ephrins/eph (Batlle et al, 2002;Holmberg et al, 2006) and Notch (Harada et al, 1999;Lowell et al, 2000;Conboy and Rando, 2002;Calvi et al, 2003;Conboy et al, 2003;Kumano et al, 2003;Tummers and Thesleff, 2003;Hadland et al, 2004;Fre et al, 2005;Robert-Moreno et al, 2005;van Es et al, 2005;Spradling, 2006, 2007;Song et al, 2007). These signaling mechanisms may occur between stem cells, between support cells and stem cells, and between stem cells and differentiating cells.…”

Notch-HES1 signaling axis controls hemato-endothelial fate decisions of human embryonic and induced pluripotent stem cells

“…For example, gene deletion studies in both zebra fish and mice have demonstrated a potential role for Notch signaling in hematopoietic and endothelial development. [4][5][6]8,9,25,39 In addition, both Notch1 and Jagged1 are implicated in the induction of definitive over primitive hematopoiesis. 4,16,25 Notch1-deficient mouse embryonic stem cells contribute to primitive yolk-sac hematopoiesis in chimeric mice but are incapable of adult blood development, 4 whereas Jagged1 is required for the establishment of definitive mouse hematopoietic precursors.…”

“…[4][5][6]8,9,25,39 In addition, both Notch1 and Jagged1 are implicated in the induction of definitive over primitive hematopoiesis. 4,16,25 Notch1-deficient mouse embryonic stem cells contribute to primitive yolk-sac hematopoiesis in chimeric mice but are incapable of adult blood development, 4 whereas Jagged1 is required for the establishment of definitive mouse hematopoietic precursors. 25 Controlling lineage specification from hPSCs remains a primary goal of regenerative medicine research; however, few reports have used exogenous factors to control cell fate commitment to one lineage over another.…”

“…[1][2][3] Notch signaling has also been shown to play an important role in the regulation of endothelial and hematopoietic cell fates in both invertebrates and mice. 4,5 Perturbation of Notch signaling has deleterious effects on embryonic hematopoiesis and vascular development. [6][7][8][9][10][11] In mouse models, Notch1 was shown to be required for generation of hematopoietic cells from bipotent hemogenic endothelial precursors, known as hemangioblasts.…”