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. 2024 Sep 11;56(1):2404186.
doi: 10.1080/07853890.2024.2404186. Epub 2024 Sep 16.

Tibial transverse transport promotes wound healing in diabetic foot ulcers by stimulating endothelial progenitor cell mobilization and homing mediated neovascularization

Weiqing Tian  1 , Lan Zhang  1 , Yongjun Wang  1 , Ligong Lin  1 , Wei Jiang  1 , Guangming Dai  1 , Bo Feng  1
Affiliations

Tibial transverse transport promotes wound healing in diabetic foot ulcers by stimulating endothelial progenitor cell mobilization and homing mediated neovascularization

Weiqing Tian et al. Ann Med. .

Abstract

Background: Diabetic foot ulcers (DFUs) are a common and serious complication of diabetes, often leading to amputation and decreased quality of life. Current treatment methods have limited success rates, highlighting the need for new approaches. This study investigates the potential of tibial transverse transport (TTT) to promote wound healing in DFUs.

Methods: To test this hypothesis, the study used New Zealand White rabbits to establish a diabetic model and simulate foot ulcers, followed by the treatment of unilateral TTT or bilateral TTT. The study employed histological analysis, flow cytometry, ELISA, and qPCR to assess the impact of TTT on tissue repair and endothelial progenitor cell (EPC) mobilization and homing, aiming to understand the underlying biological processes in wound healing.

Results: TTT significantly enhanced wound healing in diabetic rabbit foot ulcers. Specifically, bilateral TTT led to complete wound healing by day 19, faster than the unilateral TTT group, which healed by day 26, and the sham operation group, which nearly healed by day 37. Histological analysis showed improved tissue architecture, collagen deposition, and neovascularization in TTT-treated groups. Furthermore, TTT treatment resulted in a significant increase in VEGFR2 expression and VEGFR2/Tie-2 positive cells, particularly in the bilateral group. These findings were corroborated by qPCR results, which showed increased expression of VEGFA and CXCL12 by TTT. Conclusions: TTT may be a promising treatment for DFUs, significantly enhancing wound healing by stimulating EPC mobilization and homing mediated angiogenesis. This novel approach could substantially improve treatment outcomes for diabetic patients with chronic foot ulcers.

Keywords: Diabetic foot ulcers; Tibial transverse transport; angiogenesis; endothelial progenitor cells; wound healing.

Plain language summary

TTT accelerates wound healing in diabetic rabbit instep ulcers, with both unilateral and bilateral surgeries effective, and bilateral TTT showing enhanced efficacy.TTT boosts angiogenesis and collagen fiber formation, leading to increased granulation tissue and re-epithelialization of wounds.TTT induces the mobilization and homing of endothelial progenitor cells to promote angiogenesis and wound healing.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
TTT enhances wound healing in diabetic rabbit foot ulcers. (A) Photographs of foot wounds. (B) Statistical analysis of wound healing rate. (C) Statistical analysis of ulcer wound healing days. *, p < 0.05, ***, p < 0.001 compared to the sham group or unilateral TTT group.
Figure 2.
Figure 2.
The effect of TTT on angiogenesis and collagen fiber formation. (A) HE staining for granulation tissue deposition and epidermal regeneration. Scar bar = 200 or 50 μm. (B) Masson’s trichrome staining for collagen fiber formation. Scar bar = 100 or 50 μm. (C) Immunofluorescence for CD31 expression changes, anti-CD31 antibody and DAPI to the nuclei, and the arrow to indicate positive staining. Scar bar = 50 μm. (D) Immunofluorescence for VEGFA expression changes, anti-VEGFA antibody and DAPI to the nuclei, and the arrow to indicate positive staining. Scar bar = 50 μm. **, p < 0.01, ***, p < 0.001 compared to the sham group or unilateral TTT group.
Figure 3.
Figure 3.
The impact of TTT on EPC mobilization and homing. (A) Immunofluorescence for VEGFR2 expression, anti-VEGFR2 antibody and DAPI to the nuclei, and the arrow to indicate positive staining. Scale bar = 50 μm. (B) Flow cytometry analysis of peripheral blood VEGFR2/Tie-2 positive ratio. *, p < 0.05, **, p < 0.01, ***, p < 0.001 compared to the sham group or unilateral TTT group.
Figure 4.
Figure 4.
The effect of TTT on VEGFA and CXCL12 expression (A) ELISA for serum levels of VEGFA and CXCL12. (B) qPCR for skin tissue expression of VEGFA and CXCL12. *, p < 0.05, **, p < 0.01, ***, p < 0.001 compared to the sham group or unilateral TTT group.
Figure 5.
Figure 5.
Mechanism diagram of TTT promoting wound healing in DFUs (by figdraw). TTT induces wound fibroblasts to release VEGFA and CXCL12, thereby mediating EPC mobilization and homing, promoting angiogenesis and wound healing.
See this image and copyright information in PMC

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Grants and funding

This work was supported by Natural Science Foundation of Inner Mongolia Autonomous Region (2022QN08023).