Bone Morphogenetic Protein 9 Regulates Early Lymphatic-Specified Endothelial Cell Expansion during Mouse Embryonic...

Area of Science:

• Developmental biology
• Stem cell biology
• Vascular biology

Background:

• The regulation of early lymphatic development by external signals is not well understood.
• Investigating these signals is crucial for understanding lymphatic system formation and potential therapeutic interventions.

Purpose of the Study:

• To investigate the role of exogenous cues in the initial stages of lymphatic endothelial development.
• To explore the effects of bone morphogenetic protein 9 (BMP9) on lymphatic specification and expansion using an in vitro model.

Main Methods:

• Co-culture of mouse embryonic stem cell (ESC)-derived vascular precursors with OP9 stromal cells.
• Dose-dependent application of BMP9 and assessment of lymphatic progeny.
• Analysis of calcineurin phosphatase/NFATc1 signaling pathway activation.
• RNA-silencing experiments to identify receptor involvement (ALK1, ALK2).

Main Results:

• BMP9 exhibited a dose-dependent biphasic effect on ESC-derived vascular precursors.
• Low BMP9 concentrations (<1 ng/mL) expanded LYVE-1-positive lymphatic cells and activated the calcineurin phosphatase/NFATc1 pathway.
• High BMP9 concentrations promoted LYVE-1-negative endothelial cell formation, mediated by OP9 stromal cell-secreted VEGF-A.
• ALK1 and ALK2 receptors were specifically involved in BMP9 responses.

Conclusions:

• Low-dose BMP9 can promote the expansion of lymphatic endothelial cells from stem cells.
• This suggests BMP9 as a potential tool for cell-replacement strategies in lymphatic disorders.
• BMP9's differential effects highlight the complexity of lymphatic endothelial development regulation.