ALK1 Signaling in Human Cardiac Progenitor Cells Promotes a Pro-angiogenic Secretome

Area of Science:

• Cardiovascular Biology
• Cell Signaling
• Regenerative Medicine

Background:

• Pro-angiogenic paracrine/autocrine signaling is crucial for myocardial repair in cell-based therapies.
• Activin A receptor-like type 1 (ACVRL1, ALK1) signaling is vital for cardiovascular development but its role in human therapeutic cardiac cells is unclear.

Purpose of the Study:

• To investigate the role of bone morphogenetic protein-9 (BMP9)/ALK1 signaling in human highly proliferative cells (hHiPCs) derived from epicardial tissue.
• To identify novel secreted proteins regulated by BMP9/ALK1 signaling in hHiPCs and assess their impact on angiogenesis.

Main Methods:

• Isolation and characterization of hHiPCs from adult epicardial tissue.
• In vitro treatment of hHiPCs with BMP9 and BMP10, followed by proteomic analysis of conditioned media.
• Mass spectrometry to identify secreted proteins, including sclerostin (SOST), meflin (ISLR), and insulin-like growth factor binding protein-3 (IGFBP3).
• Assessment of BMP9/ALK1 signaling inhibition on protein secretion and angiogenesis.
• In vitro assays on human endothelial cells (ECs) and hHiPCs to evaluate the pro-angiogenic effects of hHiPC secretome and SOST.

Main Results:

• BMP9/ALK1 signaling regulates the secretion of SOST, ISLR, and IGFBP3 in hHiPCs.
• Inhibition of ALK1 suppressed the BMP9-induced transcription and secretion of these proteins.
• The BMP9-treated hHiPC secretome enhanced capillary-like tube formation in ECs and hHiPCs.
• Recombinant SOST treatment increased VEGF-a expression, tube formation, and annexin A2 (ANXA2) expression in hHiPCs.

Conclusions:

• BMP9/ALK1 signaling mediates the secretion of specific proteins (SOST, ISLR, IGFBP3) from hHiPCs.
• These secreted proteins play a role in paracrine/autocrine-mediated angiogenesis.
• The findings highlight the therapeutic potential of targeting BMP9/ALK1 signaling in hHiPCs for cardiac repair and vascularization.