Characterization of Multicellular Niches Supporting Hematopoietic Stem Cells Within Distinct Zones

Area of Science:

• Hematology
• Stem Cell Biology
• Developmental Biology

Background:

• Previous hematopoietic stem cell (HSC) niche research relied on single-cell models, yielding inconsistent results.
• The fetal liver (FL) is a critical site for fetal hematopoiesis, but its niche organization remains incompletely understood.

Purpose of the Study:

• To investigate the multicellular niche organization of the fetal liver and its impact on hematopoietic stem cell regulation using spatial transcriptomics.
• To compare fetal liver niches with those identified in the adult bone marrow.

Main Methods:

• Spatial transcriptomics was employed to analyze the cellular composition and spatial organization of the fetal liver.
• Gene expression analysis, including Cxcl12 and Cdh2 (encoding N-cadherin), was performed to understand niche-specific regulation.
• HSC localization and proliferation states were assessed in relation to identified niche components.

Main Results:

• Two distinct fetal liver niches were identified: the portal-vessel (PV) niche supporting quiescent HSCs and the sinusoidal niche supporting proliferative, myeloid-biased HSCs.
• N-cadherin (N-cad) expression in the PV niche is crucial for maintaining HSC quiescence; its modulation alters HSC localization and promotes myeloid bias.
• Adult bone marrow also exhibits distinct niches (trabecular bone area and central marrow) supporting HSCs in different cycling states.

Conclusions:

• The fetal liver harbors distinct multicellular niches that differentially regulate hematopoietic stem cell states (quiescent vs. proliferative).
• Niche composition and specific molecular cues, like N-cadherin, play critical roles in controlling HSC localization, proliferation, and lineage potential.
• This study advances the understanding of HSC regulation by highlighting the importance of multicellular niche organization in distinct anatomical zones, applicable to both fetal and adult hematopoietic sites.