The Potential of Mesenchymal Stem/Stromal Cells in Diabetic Wounds and Future Directions for Research and Therapy-Is It Time for Use in Everyday Practice?

Abstract

The treatment of diabetic wounds is impaired by the intricate nature of diabetes and its associated complications, necessitating novel strategies. The utilization of mesenchymal stem/stromal cells (MSCs) as a therapeutic modality for chronic and recalcitrant wounds in diabetic patients is an active area of investigation aimed at enhancing its therapeutic potential covering tissue regeneration. The threat posed to the patient and their environment by the presence of a diabetic foot ulcer (DFU) is so significant that any additional therapeutic approach that opens new pathways to halt the progression of local changes, which subsequently lead to a generalized inflammatory process, offers a chance to reduce the risk of amputation or even death. This article explores the potential of MSCs in diabetic foot ulcer treatment, examining their mechanisms of action, clinical application challenges, and future directions for research and therapy.

Keywords: ATMP; allogenic cell therapy; cell therapy; diabetic foot ulcer; mesenchymal stem/stromal cells.

Figure 1

Ilustration of pathophysiological factors that contribute to the development of neuropathy in diabetic foot syndrome.

Figure 2

MSCs role in wound healing is based on the modulation of three key phases: the inflammatory phase, where MSCs reduce inflammation via cytokine regulation and macrophage polarization; the proliferation phase, where MSCs enhance fibroblast activity and angiogenesis through VEGF and FGF signaling; and the remodeling phase, where MSCs regulate extracellular matrix breakdown and keratinocyte migration to promote tissue regeneration.

Figure 3

Number of MSC-related clinical trials found in clinicaltrials.gov database with “cell therapy” keyword, and “completed” filter. Clinical trials were divided according to the declared trial phase into: early phase 1; phase 1/2; phase 2; phase 2/3; phase 3; and phase 4. †—“N/A” trial phase information was deemed “not applicable” in clinicaltrials.gov; ††—“N/D” no data were provided regarding the trial phase in clinicaltrials.gov database.

Figure 4

An exemplary route of biological material for ATMP in connection with legal regulations. Only the most fundamental regulations are indicated.

Figure 5

A comparison of three different scaffolds used in tissue engineering: hydrogel scaffolds, known for their biodegradability, cellular survival promotion, and exosome stability; gelatin-sericin scaffolds, which offer high cellular affinity, induce reactive oxygen species (ROS) clearance, and enhance fibroblast and keratinocyte proliferation; and silk fibroin/chitosan scaffolds, which accelerate angiogenesis and stimulate the expression of growth factors like EGF, VEGF, and TGF-β, crucial for tissue regeneration.