Molecular Modulation of Fetal Liver Hematopoietic Stem Cell Mobilization into Fetal Bone Marrow in Mice

Abstract

Development of hematopoietic stem cells is a complex process, which has been extensively investigated. Hematopoietic stem cells (HSCs) in mouse fetal liver are highly expanded to prepare for mobilization of HSCs into the fetal bone marrow. It is not completely known how the fetal liver niche regulates HSC expansion without loss of self-renewal ability. We reviewed current progress about the effects of fetal liver niche, chemokine, cytokine, and signaling pathways on HSC self-renewal, proliferation, and expansion. We discussed the molecular regulations of fetal HSC expansion in mouse and zebrafish. It is also unknown how HSCs from the fetal liver mobilize, circulate, and reside into the fetal bone marrow niche. We reviewed how extrinsic and intrinsic factors regulate mobilization of fetal liver HSCs into the fetal bone marrow, which provides tools to improve HSC engraftment efficiency during HSC transplantation. Understanding the regulation of fetal liver HSC mobilization into the fetal bone marrow will help us to design proper clinical therapeutic protocol for disease treatment like leukemia during pregnancy. We prospect that fetal cells, including hepatocytes and endothelial and hematopoietic cells, might regulate fetal liver HSC expansion. Components from vascular endothelial cells and bones might also modulate the lodging of fetal liver HSCs into the bone marrow. The current review holds great potential to deeply understand the molecular regulations of HSCs in the fetal liver and bone marrow in mammals, which will be helpful to efficiently expand HSCs in vitro.

Figure 1

Microenvironment in the fetal liver is crucial for HSC proliferation. SCF ⁺ DLK ⁺ cells secret Angptl2, Angptl3, IGF2, and TPO to accelerate HSC proliferation in the fetal liver. Nestin⁺NG2⁺ pericytes associated with portal vessels is a fetal liver niche, supporting HSC expansion. Fetal liver endothelial cell produces SDF-1α favoring HSC mobilization. Loss of ATF4 in the fetal liver niche reduces HSC expansion through decreasing Angptl3, IGF2, and VEGFA.

Figure 2

Notch1 transcriptional activation domain is essential for HSC expansion in the mouse fetal liver. Upon Notch1 activation, Notch1 intracellular domain (Notch1-ICN) gets into the nucleus forming complex with RBPJ and MAML, which increases expression of Notch1 downstream target genes and fetal HSC expansion. Loss of Notch1 transcriptional activation domain (Notch1ΔTAD/ΔTAD) leads to the failure of formation of Notch1-ICN/RBPJ/MAML transcription complex, which decreases the expression of Notch1 downstream target genes, resulting in HSC apoptosis.

Figure 3

Endochondral ossification and vessel formation are required for lodgment of fetal liver HSC into the fetal bone marrow. Consistent levels of VEGF benefit vascularization in the fetal bone via binding with Flt-1 and Flk-1 receptors in endothelial cells. Vascularization in the fetal bone provides nutrition and aid niche formation. Loss of Osterix and collagen X negatively affects fetal liver HSC mobilization into the bone marrow through disrupting endochondral ossification.

Figure 4

Adhesion molecules regulate fetal liver HSC mobilization into the fetal bone marrow. Increasing levels of MMP2, Robo4, L-selectin, VLA5, and N-cadherin in fetal bone marrow HSCs are involved in HSC mobilization from the fetal liver. Decreasing VE-cadherin expression in fetal HSCs favors HSC mobilization from the fetal liver.

Figure 5

WAVE2 complex regulates fetal liver HSC mobilization into the bone marrow by modulating c-Abl signaling. Loss of Hem1 leads to degradation of WAVE2 complex without affecting actin polymerization in fetal liver HSCs. Lodgment of fetal liver HSCs into the bone marrow is impaired under Hem1 mutation, which is related to inhibiting c-Abl signaling pathway activation with decreasing phosphorylated CrkL (pCrkL).