Keratinocyte Microvesicles Regulate the Expression of Multiple Genes in Dermal Fibroblasts.
Extracellular vesicles released from cells regulate many normal and pathological conditions. Little is known about the role of epidermal keratinocyte microvesicles (KC-MVs) in epithelial-stromal interaction that is essential for wound healing. We investigated, therefore, whether MV-like structures are present in human wounds and whether they affect wound healing-associated gene expression in dermal fibroblasts. In human wounds, MV-like vesicles were observed during active epithelial migration and early granulation tissue formation. When KC-MVs derived from keratinocyte-like cells (HaCaT) were added to fibroblast cultures, expression of 21 genes was significantly regulated (P<0.05) out of 80 genes investigated, including matrix metalloproteinase-1 and -3, interleukin-6 and -8, and genes associated with transforming growth factor-β signaling. Similar changes were observed at the protein level. MVs from normal epidermal keratinocytes showed similar response to HaCaT cells. KC-MVs activated ERK1/2, JNK, Smad, and p38 signaling pathways in fibroblasts with ERK1/2 signaling having the most prominent role in the MV-induced gene expression changes. KC-MVs stimulated fibroblast migration and induced fibroblast-mediated endothelial tube formation but did not affect collagen gel contraction by fibroblasts. The results demonstrate that keratinocyte microvesicles have a strong and a specific regulatory effect on fibroblasts that may modulate several aspects of wound healing.
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, British Columbia, Canada; Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Ping
P
Huang
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, British Columbia, Canada.
Jiarui
J
Bi
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, British Columbia, Canada.
Gethin R
GR
Owen
Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Weimin
W
Chen
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
Anne
A
Rokka
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, British Columbia, Canada.
Leeni
L
Koivisto
Department of Biochemistry, University of Turku, Turku, Finland.
Jyrki
J
Heino
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, British Columbia, Canada.
Lari
L
Häkkinen
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: larjava@dentistry.ubc.ca.
Hannu
H
Larjava
D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000502:physiology* / Q000648:ultrastructure; D020935:MAP Kinase Signaling System; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology; D014945:Wound Healing
D016212:Transforming Growth Factor beta; D048049:Extracellular Signal-Regulated MAP Kinases