Diabetic wound healing: The impact of diabetes on myofibroblast activity and its potential therapeutic treatments

Abstract

Diabetes is a systemic disease in which the body cannot regulate the amount of sugar, namely glucose, in the blood. High glucose toxicity has been implicated in the dysfunction of diabetic wound healing, following insufficient production (Type 1) or inadequate usage (Type 2) of insulin. Chronic non-healing diabetic wounds are one of the major complications of both types of diabetes, which are serious concerns for public health and can impact the life quality of patients significantly. In general, diabetic wounds are characterized by deficient chemokine production, an unusual inflammatory response, lack of angiogenesis and epithelialization, and dysfunction of fibroblasts. Increasing scientific evidence from available experimental studies on animal and cell models strongly associates impaired wound healing in diabetes with dysregulated fibroblast differentiation to myofibroblasts, interrupted myofibroblast activity, and inadequate extracellular matrix production. Myofibroblasts play an important role in tissue repair by producing and organizing extracellular matrix and subsequently promoting wound contraction. Based on these studies, hyperglycaemic conditions can interfere with cytokine signalling pathways (such as growth factor-β pathway) affecting fibroblast differentiation, alter fibroblast apoptosis, dysregulate dermal lipolysis, and enhance hypoxia damage, thus leading to damaged microenvironment for myofibroblast formation, inappropriate extracellular matrix modulation, and weakened wound contraction. In this review, we will focus on the current available studies on the impact of diabetes on fibroblast differentiation and myofibroblast function, as well as potential treatments related to the affected pathways.

A story of fibers and stress: Matrix‐embedded signals for fibroblast activation in the skin

“…27 At the opposite end of myofibroblast dysfunctions in skin are chronic wounds which fail to heal due to the lack of ECM reconstitution, associated with chronic infection and inflammation. 28,29 After providing an overview on the major fibrillar ECM components in normal skin, we will briefly address the origins and heterogeneity of skin fibroblasts. We then proceed to examine the role of the ECM as cell-signaling hub with an emphasis on how fibroblasts respond to ECM mechanics to restore order in the confusing environment of a healing wound.…”

Recovery of Altered Diabetic Myofibroblast Heterogeneity and Gene Expression Are Associated with CD301b+ Macrophages

“…While a reduction in proliferation phase myofibroblasts has been documented in wound beds from diabetic mice [ 28 ], little is known about how individual subsets of myofibroblasts are altered by diabetes. We have previously described multiple subsets of myofibroblasts that can be identified using cell surface marker expression of CD29, SCA1, and CD34 [ 23 , 41 ].…”

“…This challenge is compounded by the inability to identify a chronic or nonhealing wound patient until months after the injury [ 33 ]. At this late time point after injury, the cellular and molecular interactions dictating local cellular responses are different than what is observed during normal acute repair [ 28 ]. Using a 4 mm dorsal skin excision wound model, we examined repair at multiple time points during the proliferation phase to define how myofibroblast heterogeneity is altered in db/db mice compared to db/+ control animals.…”

“…Diabetic wound healing is associated with reduced numbers of alpha-smooth muscle actin (SMA)-expressing myofibroblasts and changes in myofibroblast gene expression that contribute to reduced ECM deposition [ 28 , 29 , 30 , 31 , 32 ]. While impaired diabetic wound healing can result in wounds that persist for months to years in humans [ 33 ], repair in diabetic mice is typically delayed, with wounds closing by 14–28 days based on the original size and location of the injury [ 34 , 35 , 36 ].…”

Application of Electrospun Nanofiber Membrane in the Treatment of Diabetic Wounds

“…Then platelets aggregate to form blood clots at the wound and start hemostasis [19]. Finally, platelets rupture and release growth factors (such as platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), and epidermal growth factor (EGF)), thus attracting neutrophils, macrophages, and fibroblasts, which play a role in the subsequent healing phases [20][21][22][23]. [17], ACS, 2019.…”