Hematopoietic Jagged1 Is Required for the Transition of Hematopoietic Stem Cells from the Fetal Liver to the Adult Bone Marrow Niche

Abstract

Notch signaling is known to play important roles in hematopoietic development and differentiation. Notch1 is required for emergence of the definitive hematopoietic stem cells (HSCs) from the hemogenic endothelium, and we have previously shown that Notch signaling is essential for survival and function of HSCs in the fetal liver. Activation of canonical Notch signaling requires direct cellular contact; thus, the identity of the ligand and the ligand-presenting cell during hematopoietic development would provide valuable information of the Notch signaling mechanism in HSCs as well as the identity of key niche cells that drive the expansion and cell fate decisions of embryonic HSCs. In the present study, we have taken a comprehensive approach to determine the ligands and cells that initiate Notch signaling in the mouse fetal liver. To this end, we have performed single-cell PCR analysis for all Notch signaling proteins in E14.5 fetal HSCs and compared the findings to the adult bone marrow HSCs. We also have analyzed fetal liver endothelial cells for surface expression of all Notch ligands. We determined that Jagged1 (Jag1) is highly expressed in both endothelial cells as well as in fetal HSCs but not adult HSCs. We have performed conditional loss-of-function analysis of Jag1 in fetal endothelial cells using inducible Ve-cadherinCreERT2 as well as in fetal hematopoietic lineages using constitutive VavCre. Our results indicate that while loss of endothelial Jag1 has severe effects in embryonic vascular development, loss of hematopoietic Jag1 allows for normal fetal morphology, yet severely impedes the functional ability of fetal liver HSCs to expand and differentiate both in vitro and in vivo. Fetal to adult transplantation of VavCre+Jag1f/f HSCs indicated a defect in reconstitution potential of fetal HSCs that lack Jag1 expression. Our findings indicate that hematopoietic Jag1 is essential for maturation of HSCs in the fetal liver and for homing and reconstitution potential of HSCs into the post-natal bone marrow microenvironment. Disclosures No relevant conflicts of interest to declare.

Inference of cell type-specific gene regulatory networks on cell lineages from single cell omic datasets

“…31 ). Both LGALS1 67 and JAG1 68 have been shown to be involved in hematopoiesis, however, the specific roles in this process is not as well-characterized. In topic 5, we observed the persistence of an IRF8 -specific network from the HSCs/MPPs to LMPs populations, which was lost in MEMPs/GPs lineage and is consistent with our k-means analysis and our results from Buenrostro et al (Supplementary Fig.…”

Fate of hematopoietic stem cells determined by Notch1 signaling (Review)

“…Using Rag-1 -/- mouse stem cells, Stier et al ( 40 ) documented Notch1-induced reduction of in vivo differentiation and an increased stem cell population due to enhanced stem cell self-renewal. The research of Shao et al ( 41 ) revealed that endothelial Jagged1-Notch1 deficiency severely affects the development of fetal blood vessels and impedes the proliferation and differentiation of HSCs in vitro and in vivo . Additionally, it was specified that Notch1-Hes1 may act on hematopoietic precursor cells, which are produced following the fate of HSCs.…”