Role of fibroblast plasticity and heterogeneity in modulating angiogenesis and healing in the diabetic foot ulcer.

Chronic diabetic foot ulcers (DFUs) are an important clinical issue faced by clinicians despite the advanced treatment strategies consisting of wound debridement, off-loading, medication, wound dressings, and keeping the ulcer clean. Non-healing DFUs are associated with the risk of amputation, increased morbidity and mortality, and economic stress. Neo-angiogenesis and granulation tissue formation are necessary for physiological DFU healing and acute inflammation play a key role in healing. However, chronic inflammation in association with diabetic complications holds the ulcer in the inflammatory phase without progressing to the resolution phase contributing to non-healing. Fibroblasts acquiring myofibroblasts phenotype contribute to granulation tissue formation and angiogenesis. However, recent studies suggest the presence of five subtypes of fibroblast population and of changing density in non-healing DFUs. Further, the association of fibroblast plasticity and heterogeneity with wound healing suggests that the switch in fibroblast phenotype may affect wound healing. The fibroblast phenotype shift and altered function may be due to the presence of chronic inflammation or a diabetic wound microenvironment. This review focuses on the role of fibroblast plasticity and heterogeneity, the effect of hyperglycemia and inflammatory cytokines on fibroblasts, and the interaction of fibroblasts with other cells in diabetic wound microenvironment in the perspective of DFU healing. Next, we summarize secretory, angiogenic, and angiostatic phenotypes of fibroblast which have been discussed in other organ systems but not in relation to DFUs followed by the perspective on the role of their phenotypes in promoting angiogenesis in DFUs.

Clinically relevant experimental rodent models of diabetic foot ulcer.

Chronic wounds are a substantial clinical problem in diabetes and nearly 6% of diabetics suffer from foot disease including ulceration, infection, and tissue necrosis. Wound healing in diabetes is impaired and delayed and is augmented by diabetic complications. Wound healing involves complex cellular, molecular, and biochemical processes and animal models are the most suitable prototype to investigate and understand the underlying pathological changes in the process of wound healing. Animal models are also useful in evaluating the safety and efficacy of newer therapeutic agents and improving the clinical approaches for human patients with chronic ulcers. The wound healing strategies get more complicated in the presence of diabetes and its associated complication. Despite the advancement in methods of wound healing, the healing of the chronic diabetic foot ulcer (DFU) remains an important clinical problem resulting in costly and prolonged treatment and poses a risk for major amputation. Saying that it is important to elucidate the newer therapeutic targets and strategies via an in-depth understanding of the complicated cascade of the chronic DFU. A major challenge in translating lab findings to clinics is the lack of an optimal preclinical model capable of properly recapitulating human wounds. Both small and large animal models of wound healing involving rodents, rabbits, and pigs have been discussed. Mouse and rats as small animal models and pig as large animal models have been discussed in association with the diabetic wound but there are advantages and limitations for each model. In this review, we critically reviewed the pros and cons of experimental models of diabetic wound healing with a focus on type II diabetes rodent models.

The role of CXCL8 in chronic nonhealing diabetic foot ulcers and phenotypic changes in fibroblasts: a molecular perspective.

INTRODUCTION: A persistent inflammation is perpetuated by infiltrating immune cells and cytokines secreted from these immune cells. Additionally, apoptotic keratinocytes and adipocytes in diabetes causes diabetic foot ulcer (DFU) to arrest in an inflammatory phase without progressing to the resolution phase. This leads to a nonhealing DFU and, despite advanced treatments consisting of wound debridement, off-loading the ulcer of necrotic tissue, wound dressings to keep it moist and control exudate, medication, and preventing infection, DFUs remain a clinical problem. Nonhealing DFUs pose not only an economic burden but also increased morbidity and mortality in the form of psychological stress with and increased chance of amputation, and even death. Thus, investigating the complicated underlying molecular mechanism responsible for nonhealing patterns and designing better therapeutics is warranted. This review article focuses on the role of IL-8-mediated persistent inflammation and phenotypic change of fibroblasts due to this inflammatory cascade. We have discussed various sources of interleukin (IL)-8 secretion and the possible association of IL8-fibroblast plasticity as a cause of nonhealing DFUs. MATERIAL AND METHODS: A literature search on PubMed, Google Scholar, and PMC was done including the terms diabetic foot ulcer, diabetes, diabetic ulcer, chronic inflammation, interleukin 8, diabetic wound, and nonhealing diabetic foot ulcers. The articles in the English language and published in last 10 years were selected. From the pool of these, the articles describing the relationship between IL-8 and nonhealing diabetic foot ulcer and diabetic ulcer were used sorted out and used for this review article following PRISMA guidelines. CONCLUSION: Increased infiltration of inflammatory immune cells, secretion of pro-inflammatory cytokines, altered keratinocyte-fibroblast function, and phenotypic changes of fibroblasts in DFUs seem to be critical to the nonhealing of DFUs. Thus, inhibiting IL-8 secretion and downstream signaling seems to be a goal of potential therapeutics.

Future applications of exosomes delivering resolvins and cytokines in facilitating diabetic foot ulcer healing.

Type 2 diabetes mellitus (T2DM) increases the risk of many lethal and debilitating conditions. Among them, foot ulceration due to neuropathy, vascular disease, or trauma affects the quality of life of millions in the United States and around the world. Physiological wound healing is stalled in the inflammatory phase by the chronicity of inflammation without proceeding to the resolution phase. Despite advanced treatment, diabetic foot ulcers (DFUs) are associated with a risk of amputation. Thus, there is a need for novel therapies to address chronic inflammation, decreased angiogenesis, and impaired granulation tissue formation contributing to the non-healing of DFUs. Studies have shown promising results with resolvins (Rv) and anti-inflammatory therapies that resolve inflammation and enhance tissue healing. But many of these studies have encountered difficulty in the delivery of Rv in terms of efficiency, tissue targetability, and immunogenicity. This review summarized the perspective of optimizing the therapeutic application of Rv and cytokines by pairing them with exosomes as a novel strategy for targeted tissue delivery to treat non-healing chronic DFUs. The articles discussing the T2DM disease state, current research on Rv for treating inflammation, the role of Rv in enhancing wound healing, and exosomes as a delivery vehicle were critically reviewed to find support for the proposition of using Rv and exosomes in combination for DFUs therapy. The literature reviewed suggests the beneficial role of Rv and exosomes and exosomes loaded with anti-inflammatory agents as promising therapeutic agents in ulcer healing.

Stem Cells and Angiogenesis: Implications and Limitations in Enhancing Chronic Diabetic Foot Ulcer Healing.

Nonhealing diabetic foot ulcers (DFUs) are a continuing clinical issue despite the improved treatment with wound debridement, off-loading the ulcer, medication, wound dressings, and preventing infection by keeping the ulcer clean. Wound healing is associated with granulation tissue formation and angiogenesis favoring the wound to enter the resolution phase of healing followed by healing. However, chronic inflammation and reduced angiogenesis in a hyperglycemic environment impair the normal healing cascade and result in chronically non-healing diabetic foot ulcers. Promoting angiogenesis is associated with enhanced wound healing and using vascular endothelial growth factors has been proven beneficial to promote neo-angiogenesis. However, still, nonhealing DFUs persist with increased risks of amputation. Regenerative medicine is an evolving branch applicable in wound healing with the use of stem cells to promote angiogenesis. Various studies have reported promising results, but the associated limitations need in-depth research. This article focuses on summarizing and critically reviewing the published literature since 2021 on the use of stem cells to promote angiogenesis and enhance wound healing in chronic non-healing DFUs.

Increased Population of CD40+ Fibroblasts Is Associated with Impaired Wound Healing and Chronic Inflammation in Diabetic Foot Ulcers.

Despite the advancement in the treatment, nonhealing diabetic foot ulcers (DFUs) are an important clinical issue accounting for increased morbidity and risk of amputation. Persistent inflammation, decreased granulation tissue formation, decreased neo-angiogenesis, and infections are common underlying causes of the nonhealing pattern. Fibroblasts play a critical role in granulation tissue formation and angiogenesis and mediate wound healing how fibroblasts regulate inflammation in nonhealing DFUs is a question to ponder. This study aims to investigate the expression of a de-differentiated subpopulation of fibroblasts which are CD40+ (secretory fibroblasts) and increased secretion of IL-6 and IL-8 but have never been reported in DFUs. We characterized 11 DFU tissues and nearby clean tissues histologically and for the presence of inflammation and CD40+ fibroblasts using immunohistochemistry and RT-PCR. The results revealed significantly increased density of CD40+ fibroblasts and differential expression of mediators of inflammation in DFU tissues compared to clean tissue. Increased expression of IL-6, IL-1ß, and TNF-α in DFU tissues along with CD40+ fibroblast suggest that CD40+ fibroblasts in DFUs contribute to the chronicity of inflammation and targeting fibroblasts phenotypic switch to decrease secretory fibroblasts may have therapeutic significance to promote healing.