PMID- 33446687
OWN - NLM
STAT- MEDLINE
DCOM- 20210916
LR  - 20230127
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 11
IP  - 1
DP  - 2021 Jan 14
TI  - Dermal fibroblasts cultured from donors with type 2 diabetes mellitus retain an 
      epigenetic memory associated with poor wound healing responses.
PG  - 1474
LID - 10.1038/s41598-020-80072-z [doi]
LID - 1474
AB  - The prevalence of Type 2 diabetes mellitus (T2DM) is escalating globally. 
      Patients suffer from multiple complications including the development of chronic 
      wounds that can lead to amputation. These wounds are characterised by an 
      inflammatory environment including elevated tumour necrosis factor alpha (TNF-alpha). 
      Dermal fibroblasts (DF) are critical for effective wound healing, so we sought to 
      establish whether there were any differences in DF cultured from T2DM donors or 
      those without diabetes (ND-DF). ND- and T2DM-DF when cultured similarly in vitro 
      secreted comparable concentrations of TNF-alpha. Functionally, pre-treatment with 
      TNF-alpha reduced the proliferation of ND-DF and transiently altered ND-DF 
      morphology; however, T2DM-DF were resistant to these TNF-alpha induced changes. In 
      contrast, TNF-alpha inhibited ND- and T2DM-DF migration and matrix metalloprotease 
      expression to the same degree, although T2DM-DF expressed significantly higher 
      levels of tissue inhibitor of metalloproteases (TIMP)-2. Finally, TNF-alpha 
      significantly increased the secretion of pro-inflammatory cytokines (including 
      CCL2, CXCL1 and SERPINE1) in ND-DF, whilst this effect in T2DM-DF was blunted, 
      presumably due to the tendency to higher baseline pro-inflammatory cytokine 
      expression observed in this cell type. Collectively, these data demonstrate that 
      T2DM-DF exhibit a selective loss of responsiveness to TNF-alpha, particularly 
      regarding proliferative and secretory functions. This highlights important 
      phenotypic changes in T2DM-DF that may explain the susceptibility to chronic 
      wounds in these patients.
FAU - Al-Rikabi, Aaiad H A
AU  - Al-Rikabi AHA
AD  - Centre for Skin Sciences, Faculty of Life Sciences, University of Bradford, 
      Bradford, UK.
AD  - Department of Biology, College of Science, University of Baghdad, Baghdad, Iraq.
FAU - Tobin, Desmond J
AU  - Tobin DJ
AD  - The Charles Institute for Dermatology, School of Medicine, University College 
      Dublin, Dublin, Ireland.
FAU - Riches-Suman, Kirsten
AU  - Riches-Suman K
AD  - Centre for Skin Sciences, Faculty of Life Sciences, University of Bradford, 
      Bradford, UK.
FAU - Thornton, M Julie
AU  - Thornton MJ
AD  - Centre for Skin Sciences, Faculty of Life Sciences, University of Bradford, 
      Bradford, UK. m.j.thornton@bradford.ac.uk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210114
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Cytokines)
RN  - 0 (Tissue Inhibitor of Metalloproteinases)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Cells, Cultured
MH  - Cytokines/metabolism
MH  - Diabetes Mellitus, Type 2/*genetics/metabolism/physiopathology
MH  - Epigenesis, Genetic/genetics
MH  - Epigenomics/methods
MH  - Female
MH  - Fibroblasts/metabolism
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Primary Cell Culture
MH  - Skin/*metabolism
MH  - Tissue Inhibitor of Metalloproteinases/metabolism
MH  - Tumor Necrosis Factor-alpha/analysis/metabolism
MH  - Wound Healing/*genetics
PMC - PMC7809350
COIS- The authors declare no competing interests.
EDAT- 2021/01/16 06:00
MHDA- 2021/09/18 06:00
PMCR- 2021/01/14
CRDT- 2021/01/15 05:54
PHST- 2020/06/04 00:00 [received]
PHST- 2020/12/02 00:00 [accepted]
PHST- 2021/01/15 05:54 [entrez]
PHST- 2021/01/16 06:00 [pubmed]
PHST- 2021/09/18 06:00 [medline]
PHST- 2021/01/14 00:00 [pmc-release]
AID - 10.1038/s41598-020-80072-z [pii]
AID - 80072 [pii]
AID - 10.1038/s41598-020-80072-z [doi]
PST - epublish
SO  - Sci Rep. 2021 Jan 14;11(1):1474. doi: 10.1038/s41598-020-80072-z.