Healing Potential: Enhancing Angiogenesis with induced Mesenchymal Stem Cell release of HIF1α/VEGF in Diabetic Foot Ulcer Therapy
Vivanna Nguyen
Background: Currently, approximately 11.6% of Americans have been diagnosed with diabetes and this number continues to rise at an alarming rate.1 Diabetic foot ulcers (DFU) are a common complication of DM that are difficult to treat due to impaired wound healing as a result of hyperglycemia, peripheral arterial disease, and neuropathy. Prolonged hypoxia and hyperglycemia in diabetic patients prohibits the HIF1α dimer to stabilize and subsequently increase VEGF expression.4 Impaired macrophage switching also impairs release of proangiogenic growth factors from being released from M2 macrophages.3 DFUs are a complex therapy target due to the multifaceted problems related to chronic inflammation, decreased angiogenesis/vascularization, and impaired extracellular matrix deposition.2 Currently, the only FDA approved DFU treatment is becaplermin, a human recombinant PDGF-BB gel that has increased risks for oncogenesis, high cost, and little effect on angiogenesis.3
Objective: In this narrative review, we explore the mechanisms of increasing HIF1α and VEGF through therapy for angiogenesis in impaired wound healing of DFU patients.
Research Methods: An online search in the PubMed database was conducted with a 5 year filter using the following keywords: “diabetic foot ulcer”, “plasma”, “stem cells”, “becaplermin”, and “wound healing”.
Results: Studies have begun to look for solutions in mesenchymal stem cells that can be induced to continuously release proangiogenic growth factors in DFUs. In a study using human ABCB5+ mesenchymal stem cells, samples were collected from patients and isolated using monoclonal antibodies. The ABCB5+ MSCs were able to express HIF-1α under hypoxic conditions followed by a four fold increase in VEGF mRNA expression with subsequent increase in VEGF protein secretion. IM injections of ABCB5+ MSCs into ischemic wound induced mice compared to vehicle injection showed increased dose-dependent neovascularization and CD31 score.5 In another study, autologous platelet rich fibrin samples applied to DFUs showed significant increase in VEGF expression especially in conjunction with hyaluronic acid.6 DFUs are complex and the ability of the two therapeutic agents from these two studies shows the prospective future in combining treatments to closely mimic normal wound healing environments. Using versions of these therapeutics in combination was tested by researchers through combining the use of human placenta-derived mesenchymal stem cells (hPDMSC), gelatin nanofiber scaffolds, and platelet rich plasma (PRP). The clinical trial consisted of 28 patients with DFUs that were resistant to healing after one month of standard treatment. The patients were randomized into three different treatment groups for standard therapy (group C), hPDMSC scaffold therapy (group A), and hPDMSC scaffold with PRP gel (group B). Compared to baseline wound size, group A had a 66% reduction in size, group B had a 71% reduction, and group C had a 36% reduction in wound size. There was a significant increase in pain free walking distance in groups A and B compared to Group C.7
Conclusion: Scaffolding with biocompatible materials to mimic the extracellular matrix shows promising results especially when combined with adjunctive treatment of mediators of angiogenesis and anti-inflammation. These conditions mimic normal wound healing that can successfully progress to the proliferative and remodeling phase that DFUs cannot normally achieve.
Work Cited:
- Bandyk DF. The diabetic foot: Pathophysiology, evaluation, and treatment. Semin Vasc Surg. 2018;31(2-4):43-48. doi:10.1053/j.semvascsurg.2019.02.001
- Deng H, Li B, Shen Q, et al. Mechanisms of diabetic foot ulceration: A review. J Diabetes. 2023;15(4):299-312. doi:10.1111/1753-0407.13372
- Spampinato SF, Caruso GI, De Pasquale R, Sortino MA, Merlo S. The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs. Pharmaceuticals (Basel). 2020;13(4):60. Published 2020 Apr 1. doi:10.3390/ph13040060
- Ansari P, Akther S, Khan JT, Islam SS, Masud MSR, Rahman A, Seidel V, Abdel-Wahab YHA. Hyperglycaemia-Linked Diabetic Foot Complications and Their Management Using Conventional and Alternative Therapies. Applied Sciences. 2022; 12(22):11777.https://doi.org/10.3390/app122211777
- Kerstan A, Dieter K, Niebergall-Roth E, et al. Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers. Stem Cell Res Ther. 2022;13(1):455. Published 2022 Sep 5. doi:10.1186/s13287-022-03156-9
- Kartika RW, Alwi I, Suyatna FD, et al. The role of VEGF, PDGF and IL-6 on diabetic foot ulcer after Platelet Rich Fibrin + hyaluronic therapy. Heliyon. 2021;7(9):e07934. Published 2021 Sep 7. doi:10.1016/j.heliyon.2021.e07934
- Meamar R, Ghasemi-Mobarakeh L, Norouzi MR, Siavash M, Hamblin MR, Fesharaki M. Improved wound healing of diabetic foot ulcers using human placenta-derived mesenchymal stem cells in gelatin electrospun nanofibrous scaffolds plus a platelet-rich plasma gel: A randomized clinical trial. Int Immunopharmacol. 2021;101(Pt B):108282. doi:10.1016/j.intimp.2021.108282