Cyclophilin A modulates bone marrow-derived CD117(+) cells and enhances ischemia-induced angiogenesis via the...

Area of Science:

• Vascular Biology
• Regenerative Medicine
• Ischemia Research

Background:

• Critical limb ischemia (CLI) presents a significant therapeutic challenge due to insufficient tissue vascularization.
• Cyclophilin A (CyPA) is known to promote angiogenesis in vitro and bone marrow (BM) cell mobilization in vivo.
• The angiogenic potential of CyPA in CLI has not been previously investigated.

Purpose of the Study:

• To investigate the efficacy of Cyclophilin A (CyPA) as an angiogenic factor in ischemic tissues.
• To determine if CyPA can induce neo-angiogenesis in the context of critical limb ischemia.

Main Methods:

• Acute hind-limb ischemia (HLI) was induced in C57Bl/6j mice.
• Recombinant CyPA or saline was administered intramuscularly.
• Limb perfusion, capillary density, arteriole number, and bone marrow-derived CD117(+) cell recruitment were assessed.
• In vitro studies evaluated CyPA's effect on CD117(+) cell proliferation, death, adhesion, and migration.
• Mechanistic studies explored the role of the SDF-1/CXCR4 axis.

Main Results:

• CyPA treatment significantly increased limb perfusion, capillary density, and arteriole number in ischemic adductor muscles.
• BM-derived CD117(+) cell recruitment into ischemic tissue was significantly higher in CyPA-treated mice.
• In vitro, CyPA dose-dependently enhanced CD117(+) cell adhesion and migration, with low concentrations promoting proliferation and high concentrations causing cell death.
• CyPA upregulated CXCR4 in CD117(+) cells and ischemic muscle tissue.
• Inhibition of the SDF-1/CXCR4 axis reduced CyPA-mediated cell recruitment.

Conclusions:

• Cyclophilin A (CyPA) effectively induces neo-angiogenesis in ischemic tissues.
• CyPA facilitates this process by recruiting bone marrow-derived CD117(+) cells.
• The mechanism involves, at least in part, the SDF-1/CXCR4 signaling pathway.