Neurotrophin-3 Accelerates Wound Healing in Diabetic Mice by Promoting a Paracrine Response in Mesenchymal Stem Cells

Abstract

Angiogenesis is a major obstacle for wound healing in patients with diabetic foot wounds. Mesenchymal stem cells (MSCs) have an important function in wound repair, and neurotrophin-3 (NT-3) can promote nerve regeneration and angiogenesis. We investigated the effect of NT-3 on accelerating wound healing in the diabetic foot by improving human bone marrow MSC (hMSC) activation. In vitro, NT-3 significantly promoted VEGF, NGF, and BDNF secretion in hMSCs. NT-3 improved activation of the hMSC conditioned medium, promoted human umbilical vein endothelial cell (HUVEC) proliferation and migration, and significantly improved the closure rate of HUVEC scratches. In addition, we produced nanofiber mesh biological tissue materials through the electrospinning technique using polylactic acid, mixed silk, and collagen. The hMSCs stimulated by NT-3 were implanted into the material. Compared with the control group, the NT-3-stimulated hMSCs in the biological tissue material significantly promoted angiogenesis in the feet of diabetic C57BL/6J mice and accelerated diabetic foot wound healing. These results suggest that NT-3 significantly promotes hMSC secretion of VEGF, NGF, and other vasoactive factors and that it accelerates wound healing by inducing angiogenesis through improved activation of vascular endothelial cells. The hMSCs stimulated by NT-3 can produce materials that accelerate wound healing in the diabetic foot and other ischemic ulcers.

Wharton's jelly derived mesenchymal stromal cells: Biological properties, induction of neuronal phenotype and current applications in neurodegeneration research

“…• Easily expanded from adult and fetal tissues • Multilineage capabilities • Immune privileged cells • Immunomodulatory and anti-proliferative action • Release of trophic factors • Homing to damaged sites that MSC may exert a beneficial trophic effect on injured tissues, even without necessarily replacing dying cells (Crigler et al, 2006;Shen et al, 2013). Thus, some characteristics of MSCs make these cells even more promising for the development of cell therapies (Box 1).…”

Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer

“…O'Loughlin and colleagues indicated that allogeneic BM-MSCs seeded in a collagen scaffold could improve wound healing by augmenting angiogenesis in diabetic rabbit ear ulcer model [55]. In the study of diabetic mice, neurotrophin-3- (NT-3-) stimulated human BM-MSCs in the biological tissue material expressed VEGF, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and other vascular endothelial factors to upregulate angiogenesis and thicken granulation tissue [56]. Coincidentally, the conditioned medium of heme oxygenase-1- (HO-1-) overexpressing human BM-MSCs promoted the proliferation and migration of human umbilical vein endothelial cells (HUVECs) in vitro.…”

C-X-C motif chemokine ligand 8 promotes endothelial cell homing via the Akt-signal transducer and activator of transcription pathway to accelerate healing of ischemic and hypoxic skin ulcers

“…Images of the cells were captured using a BX83 fluorescence microscope (Olympus Corporation). Image-Pro Plus 7.0 software (Media Cybernetics, Inc.) was used to measure the cell scratch area at 0 h and 24 h, and the wound closure rate was calculated, as previously described (20).…”

“…After 8 h of incubation at 37˚C in normoxic or hypoxic conditions, cells in the upper compartment were removed, while migrated cells in the lower compartment were washed three times with 0.01 mmol/l PBS, then fixed with 4% paraformaldehyde at room temperature for 4 h, stained with 0.5% crystal violet and imaged using the BX83 microscope. Image-Pro Plus 7.0 software (Media Cybernetics, Inc.) was used to calculate the number of cells and the cell migration rate, as described previously (20,21).…”