Migratory, metabolic and functional alterations of fibrocytes in type 2 diabetes.

Fibrocytes are bloodborne mesenchymal progenitor cells that are recruited to injured tissue sites and contribute to the repair process by acquiring a myofibroblast-like phenotype and producing extracellular matrix components and growth factors. Treatment with normal fibrocytes or their exosomes restores the ability of genetically diabetic mice to heal skin wounds, suggesting the existence of dysfunctional alterations in diabetic fibrocytes. This study compared the migratory, metabolic and functional characteristics of fibrocytes from patients with type 2 diabetes (T2DPs) and healthy controls (HCs). It was found that the frequency of these cells was abnormally low in the peripheral blood of T2DPs. Diabetic fibrocytes showed reduced expression of the C-X-C motif and C-C motif chemokine receptors (CXCR)4, (CCR)5, and CCR7, and demonstrated reduced migration in response to their ligands (CXCL)12, (CCL)5, and CCL21. They exhibited increased expression of the receptor for advanced glycation end product, suppression of the alternative AGE receptor 1, increased intracellular concentrations of AGEs, decreased expression of sirtuin-1 and elevated oxidative stress. In short-term cultures, fibrocytes from T2DPs released larger amounts of proinflammatory cytokines than those from HCs. Unlike normal fibrocytes, diabetic fibrocytes did not exhibit increased expression of type I collagen and α-smooth muscle actin on stimulation with transforming growth factor (TGF)-ß1 and this abnormal response was associated with downregulation of TGF-ß1 type II receptor on the cell surface. Study findings uncover multiple migratory and functional alterations of diabetic fibrocytes that may contribute to explain why T2DPs experience impaired wound healing and chronic ulcers. © 2018 IUBMB Life, 70(11):1122-1132, 2018.

Human fibrocyte-derived exosomes accelerate wound healing in genetically diabetic mice.

Diabetic ulcers represent a substantial societal and healthcare burden worldwide and scarcely respond to current treatment strategies. This study was addressed to evaluate the therapeutic potential of exosomes secreted by human circulating fibrocytes, a population of mesenchymal progenitors involved in normal wound healing via paracrine signaling. The exosomes released from cells sequentially stimulated with platelet-derived growth factor-BB and transforming growth factor-ß1, in the presence of fibroblast growth factor 2, did not show potential immunogenicity. These exosomes exhibited in-vitro proangiogenic properties, activated diabetic dermal fibroblasts, induced the migration and proliferation of diabetic keratinocytes, and accelerated wound closure in diabetic mice in vivo. Important components of the exosomal cargo were heat shock protein-90α, total and activated signal transducer and activator of transcription 3, proangiogenic (miR-126, miR-130a, miR-132) and anti-inflammatory (miR124a, miR-125b) microRNAs, and a microRNA regulating collagen deposition (miR-21). This proof-of-concept study demonstrates the feasibility of the use of fibrocytes-derived exosomes for the treatment of diabetic ulcers.