HTATIP2 regulates arteriogenic activity in monocytes from patients with limb ischemia

Area of Science:

• Regenerative Medicine
• Vascular Biology
• Cell Therapy

Background:

• Cell therapy for chronic limb-threatening ischemia (CLTI) shows modest efficacy, potentially due to impaired autologous cells.
• Proarteriogenic monocyte/macrophages (Mo/MΦs) play a crucial role in neovascularization and arteriogenesis.

Purpose of the Study:

• To investigate functional impairments in proarteriogenic Mo/MΦs from CLTI patients.
• To elucidate the underlying mechanisms of Mo/MΦ dysfunction in CLTI.
• To assess the therapeutic potential of modulating these mechanisms.

Main Methods:

• Isolation and characterization of proarteriogenic Mo/MΦs from CLTI patients and healthy controls.
• In vitro and in vivo assays to evaluate neovascularization and arteriogenesis capacity.
• Gene silencing of HTATIP2 (human HIV-1 TAT interactive protein-2) and assessment of downstream effects on angiogenic/arteriogenic regulators and processes.

Main Results:

• CLTI Mo/MΦs exhibited impaired neovascularization capacity compared to controls.
• Increased HTATIP2 expression in CLTI Mo/MΦs was associated with suppressed angiogenesis/arteriogenesis.
• Silencing HTATIP2 restored Mo/MΦ function, increasing Neuropilin-1 and Angiopoietin-1 expression and enhancing endothelial tubule formation and smooth muscle proliferation.
• In vivo, HTATIP2 silencing in CLTI Mo/MΦs improved limb perfusion through enhanced angiogenesis and arteriogenesis.

Conclusions:

• Proarteriogenic Mo/MΦs from CLTI patients are functionally impaired, partly due to elevated HTATIP2.
• Ex vivo modulation of HTATIP2 can restore the therapeutic potential of autologous Mo/MΦs for CLTI.
• Targeting HTATIP2 represents a promising strategy to improve cell therapy efficacy in CLTI patients.