Engineering a multicellular vascular niche to model hematopoietic cell trafficking

Area of Science:

• Biomedical Engineering
• Hematology
• Cell Biology

Background:

• The bone marrow microenvironment and vasculature are crucial for hematopoietic cell regulation.
• Current in vitro models lack complex multicellular interactions and in vivo studies are difficult to manipulate.
• Understanding these interactions is key for hematopoiesis and stem cell research.

Purpose of the Study:

• To develop an engineered human vascular marrow niche for studying three-dimensional cell interactions.
• To examine how these interactions direct hematopoietic cell trafficking.
• To provide a platform for investigating normal and diseased marrow environments.

Main Methods:

• Fabricated endothelialized vascular networks in a collagen matrix using soft lithography and injection molding.
• Co-cultured vascular networks with marrow fibroblast cells (mesenchymal stem cells (MSCs), HS27a, HS5) under flow.
• Evaluated interactions, gene expression, and hematopoietic cell adhesion/migration using confocal microscopy and RT-PCR.

Main Results:

• Marrow fibroblasts (HS27a, MSCs) showed differential interaction with the vessel wall compared to HS5 cells.
• Endothelial junctional marker expression decreased in HS27a and HS5 co-cultures.
• HS27a co-cultures promoted monocyte adhesion and migration; hematopoietic progenitors relied on monocyte-fibroblast crosstalk for recruitment.
• Leukemic cells were recruited to both HS5 and HS27a co-cultures, but monocytes could inhibit this sensitivity.

Conclusions:

• Demonstrated a microvascular platform for studying hematopoietic cell trafficking with tunable multicellular composition.
• Highlighted the complexity of cell-cell interactions in the marrow, influencing differential hematopoietic cell recruitment.
• The platform allows step-wise incorporation of cells to reveal dynamic interactions within the marrow vascular niche.
• The platform shows potential for therapeutic testing and personalized medicine in various disease contexts.