Obesity/Type II Diabetes Alters Macrophage Polarization Resulting in a Fibrotic Tendon Healing Response

Abstract

Type II Diabetes (T2DM) dramatically impairs the tendon healing response, resulting in decreased collagen organization and mechanics relative to non-diabetic tendons. Despite this burden, there remains a paucity of information regarding the mechanisms that govern impaired healing of diabetic tendons. Mice were placed on either a high fat diet (T2DM) or low fat diet (lean) and underwent flexor tendon transection and repair surgery. Healing was assessed via mechanical testing, histology and changes in gene expression associated with collagen synthesis, matrix remodeling, and macrophage polarization. Obese/diabetic tendons healed with increased scar formation and impaired mechanical properties. Consistent with this, prolonged and excess expression of extracellular matrix (ECM) components were observed in obese/T2DM tendons. Macrophages are involved in both inflammatory and matrix deposition processes during healing. Obese/T2DM tendons healed with increased expression of markers of pro-inflammatory M1 macrophages, and elevated and prolonged expression of M2 macrophages markers that are involved in ECM deposition. Here we demonstrate that tendons from obese/diabetic mice heal with increased scar formation and increased M2 polarization, identifying excess M2 macrophage activity and matrix synthesis as a potential mechanism of the fibrotic healing phenotype observed in T2DM tendons, and as such a potential target to improve tendon healing in T2DM.

Effects of Type II Diabetes Mellitus on Tendon Homeostasis and Healing

“…Despite the well‐known complications that arise during diabetic tendon healing, there are few animal studies that examine the mechanisms and cell types involved in the abnormal healing response (Table ). Similar to what is seen in clinical cases of T2DM tendon injury, T2DM rodent models exhibit impaired tendon healing . More specifically, using the DIO mouse model, David et al reported increased extracellular matrix disorganization, limited tenocyte migration, and impaired biomechanical properties following a biopsy punch injury to the FDL mid‐substance.…”

“…As with human cases, the majority of diabetic mouse models are obese with varying levels of severity. Male C57BL/6J mice are commonly used to model diet‐induced obesity (DIO) and associated T2DM as they become obese and develop decreased glucose tolerance with moderate insulin resistance when fed a high‐fat diet (HFD) . The DIO mouse model also recapitulates hallmark complications of human T2DM including impaired wound healing and peripheral neuropathy .…”

The cellular basis of fibrotic tendon healing: challenges and opportunities

“…Similarly, in obese/T2DM rodents, flexor tendons heal with increased fibrosis and significantly impaired mechanical properties (75,141,142). This poor healing response is associated with increased expression of M1 macrophage markers in addition to increased and sustained expression of M2 macrophage markers throughout healing in obese/T2DM mice compared to controls (75). Though the reason for poor tendon healing in obese and/or diabetic patients is likely multifactorial, these studies further imply that inflammation is a critical driver of tendon fibrosis.…”

“…Fibrotic tendon disorders and complications during tendon healing are common in both obese and/or T2DM patients. Similarly, in obese/T2DM rodents, flexor tendons heal with increased fibrosis and significantly impaired mechanical properties (75,141,142). This poor healing response is associated with increased expression of M1 macrophage markers in addition to increased and sustained expression of M2 macrophage markers throughout healing in obese/T2DM mice compared to controls (75).…”

“…Lin et al reported that an elevated M1:M2 ratio correlated with an increase in aberrant ECM deposition following injury, implicating M1 macrophages as a driver of fibrosis in tendon healing (74). However, as in other tissues, M2 macrophages can also be pro-fibrotic in tendon (75,76). In addition to circulating macrophages recruited following injury, most tissues contain subpopulations of tissue resident macrophages (77).…”