Mesenchymal cells stimulate capillary morphogenesis via distinct proteolytic mechanisms

Area of Science:

• Cell Biology
• Biochemistry
• Tissue Engineering

Background:

• Endothelial cells (ECs) degrade extracellular matrix (ECM) during angiogenesis for invasion.
• The role of cell-cell interactions in EC proteolytic mechanisms is not fully understood.

Purpose of the Study:

• Investigate proteolytic mechanisms by which mesenchymal cells stimulate EC capillary formation.
• Elucidate the specific proteases involved in mesenchymal stem cell (MSC) and fibroblast-mediated angiogenesis.

Main Methods:

• Utilized a 3D co-culture model with ECs and either MSCs or fibroblasts.
• Analyzed EC gene expression of extracellular proteases.
• Administered broad-spectrum and specific protease inhibitors.

Main Results:

• ECs alone invaded matrix but did not form capillaries.
• Co-culture with MSCs or fibroblasts induced polarized EC tubular structures associated with mesenchymal cells.
• MSC-stimulated capillary formation depended on membrane-type matrix metalloproteinases (MT-MMPs).
• Fibroblast-mediated sprouting required inhibition of the plasminogen activator/plasmin axis, independent of MMPs.

Conclusions:

• Heterotypic cellular interactions direct proteolytic mechanisms for capillary formation.
• MSC- and fibroblast-mediated angiogenesis utilize distinct protease pathways.
• Cellular microenvironment interactions are crucial regulators of angiogenesis.