Abstract
PURPOSE: Stem cell-based therapies are considered an alternative approach for critical limb ischemia (CLI) patients with limited or exhausted options, yet their clinical use is limited by the lack of sustainability and unclear mechanism of action. In this study, a substance P-conjugated scaffold was injected with mesenchymal stem cells (MSCs) into an animal model of CLI to verify whether angiogenesis could be enhanced. METHODS: A self-assembling peptide (SAP) was conjugated with substance P, known to have the ability to recruit host stem cells into the site of action. This SAP was injected with MSCs into ischemic hindlimbs of rats, and the presence of MSCs was verified by immunohistochemical (IHC) staining of MSC-specific markers at days 7, 14, and 28. The degree of angiogenesis, cell apoptosis, and fibrosis was also quantified. RESULTS: Substance P-conjugated SAP was able to recruit intrinsic MSCs into the ischemic site of action. When injected in combination with MSCs, the presence of both injected and recruited MSCs was found in the ischemic tissues by double IHC staining. This in turn led to a higher degree of angiogenesis, less cell apoptosis, and less tissue fibrosis compared to the other groups at all time points. CONCLUSION: The combination of substance P-conjugated SAP and MSCs was able to enhance angiogenesis and tissue repair, which was achieved by the additive effect from exogenously administered and intrinsically recruited MSCs. This scaffold-based intrinsic recruitment approach could be a viable option to enhance the therapeutic effects in patients with CLI.