title: Human fibrocyte-derived exosomes accelerate wound healing in genetically diabetic mice.
abstract: 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-β1, 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.
authors.affiliation: Technology Development and Proteomics & Metabolomics Laboratory, DreiRosen Pharma GmbH, Berlin, Germany. Electronic address: ageiger@dreirosen-pharma.com.
authors.forename: Adolf
authors.initials: A
authors.lastname: Geiger
authors.affiliation: Technology Development and Proteomics & Metabolomics Laboratory, DreiRosen Pharma GmbH, Berlin, Germany. Electronic address: awalker@dreirosen-pharma.com.
authors.forename: Audrey
authors.initials: A
authors.lastname: Walker
authors.affiliation: Technology Development and Proteomics & Metabolomics Laboratory, DreiRosen Pharma GmbH, Berlin, Germany. Electronic address: enissen@dreirosen-pharma.com.
authors.forename: Erwin
authors.initials: E
authors.lastname: Nissen
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002465:Cell Movement; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055354:Exosomes / Q000737:chemistry / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000737:chemistry* / Q000166:cytology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019899:Paracrine Communication; D061251:Primary Cell Culture; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014456:Ulcer / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects
chemical_list: D018841:HSP90 Heat-Shock Proteins; C107835:Hspca protein, mouse; D035683:MicroRNAs; D020574:Proto-Oncogene Proteins c-sis; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin
keywords: Chronic wound; Diabetes; Exosome; Fibrocyte; Wound healing