MSCs modified with ACE2 restore endothelial function following LPS challenge by inhibiting the activation of RAS

Area of Science:

• Regenerative Medicine
• Vascular Biology
• Genetics

Background:

• Angiotensin II (Ang II) contributes to endothelial dysfunction in acute lung injury (ALI).
• Angiotensin-converting enzyme 2 (ACE2) degrades Ang II, but targeted therapies for ALI endothelium are limited.
• Mesenchymal stem cells (MSCs) can deliver therapeutic genes to injury sites.

Purpose of the Study:

• To evaluate the efficacy of MSCs genetically modified to overexpress ACE2.
• To assess the impact on Ang II levels and endothelial repair in lipopolysaccharide (LPS)-induced injury models.

Main Methods:

• MSCs were modified using a lentiviral vector for sustained ACE2 overexpression.
• Transduction efficiency and ACE2 expression stability were confirmed over passages.
• In vitro assays assessed endothelial cell survival, inflammatory mediator production, permeability, and VE-cadherin expression.

Main Results:

• High and stable ACE2 expression was achieved in modified MSCs.
• Modified MSCs secreted active ACE2, reducing Ang II and increasing Ang 1-7.
• ACE2-modified MSCs significantly enhanced endothelial repair markers compared to unmodified MSCs.

Conclusions:

• Sustained ACE2 overexpression in MSCs yields biologically active protein.
• ACE2-modified MSCs demonstrate superior endothelial repair capabilities.
• These findings support further investigation of ACE2-modified MSCs in ALI animal models.