CD26/DPPIV down-regulation in endometrial stromal cell migration in endometriosis.
OBJECTIVE
To test the hypothesis that endometrial stromal cells (ESCs) in endometriosis exhibit increased cell motility under hypoxia.


METHODS
Prospective case-control study.


METHODS
University research laboratory.


METHODS
Women with endometriosis (n = 18) or benign gynecological disease (n=19).


METHODS
Eutopic ESCs were cultured under normoxia (20% O2) or hypoxia (6.5% O2), and migration and invasion capacity assayed, with pathway-focused polymerase chain reaction (PCR) array and ELISAs performed. CD26/dipeptidyl peptidase IV (DPPIV) expression was determined by flow cytometric analysis and enzymatic activity assay. The ESCs supplemented with Diprotin A (CD26 inhibitor), stromal cell-derived factor-1α, or AMD3100 (C-X-C motif receptor 4; CXCR4 blocker) were assayed for their migratory potential.


METHODS
Endometrial stromal cell migration and invasion under hypoxia.


RESULTS
Endometriotic ESCs showed significantly higher migration and invasion through collagen gels under hypoxia compared with nonendometriotic ESCs. The PCR array revealed down-regulation of the migration inhibitor CD26/DPPIV and up-regulation of angiogenic factors (vascular endothelial growth factor A, C-X-C motif Ligand 6; CXCL6) in endometriotic ESCs under hypoxia. The CD26/DPPIV surface expression and activity as well as angiogenic protein secretions suggested that the molecular mechanisms underlying aberrant migratory and angiogenic behavior in endometriotic ESCs. A combinatorial treatment with diprotin A and stromal cell-derived factor-1α effectively enhanced migration and invasion preferentially in endometriotic ESCs cultured hypoxically.


CONCLUSIONS
Loss of CD26/DPPIV under hypoxia and the subsequent increase in migratory and angiogenic factors may favor conditions for lesion development in endometriosis.
BioSystems and Micromechanics, Singapore-MIT Alliance for Research & Technology, Singapore; Department of Obstetrics and Gynaecology, National University of Singapore, Singapore.
Chin Wen
CW
Tan
BioSystems and Micromechanics, Singapore-MIT Alliance for Research & Technology, Singapore.
Yie Hou
YH
Lee
Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore.
Heng Hao
HH
Tan
Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore.
Matthew Sie Kuei
MS
Lau
Department of Obstetrics and Gynaecology, National University of Singapore, Singapore.
Mahesh
M
Choolani
BioSystems and Micromechanics, Singapore-MIT Alliance for Research & Technology, Singapore; Department of Biological and Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts; Center for Gynepathology Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Linda
L
Griffith
BioSystems and Micromechanics, Singapore-MIT Alliance for Research & Technology, Singapore; Department of Obstetrics and Gynaecology, National University of Singapore, Singapore; Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore; Cancer & Stem Cell Biology Program, Duke NUS Graduate Medical School, Singapore. Electronic address: jerrychan@nus.edu.sg.
Jerry Kok Yen
JK
Chan
D000328:Adult; D016022:Case-Control Studies; D015687:Cell Hypoxia; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054427:Chemokine CXCL6 / Q000235:genetics / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D018450:Disease Progression; D015536:Down-Regulation; D004715:Endometriosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
C515503:CXCL6 protein, human; D054427:Chemokine CXCL6; D054873:Dipeptidyl-Peptidase IV Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
CD26/DPPIV; Endometriosis; endometrial stromal cells; hypoxia; migration