Myofibroblast progenitor cells are increased in number in patients with type 1 diabetes and express less bone morphogenetic protein 6: a novel clue to adverse tissue remodelling?
OBJECTIVE
Growth factor imbalance and endothelial progenitor cell dysfunction are well-known elements of the inappropriate response to injury in human and experimental diabetes. We hypothesised that in diabetes the outgrowth of myofibroblast progenitor cells (MFPCs) is also altered and that this relates to aberrant gene expression of growth factors involving members of the TGF-beta/bone morphogenetic protein (BMP) superfamily.


METHODS
MFPCs were cultured from peripheral blood mononuclear cells of patients with type 1 diabetes and control subjects. Microarray analysis, quantitative PCR and ELISA were used to identify differentially regulated TGF-beta/BMP superfamily genes in diabetes- and control-derived MFPC. Possible effects of BMP6 on TGF-beta-induced gene expression were examined in cultured renal fibroblasts (TK173 cells).


RESULTS
Blood from diabetic patients yielded higher numbers of MFPCs than blood from control subjects (1.6-fold increase, p<0.05), involving increased proliferation and decreased apoptosis. BMP6 mRNA and protein were downregulated in MFPCs derived from patients with diabetes (3.9- and 1.8-fold decrease, respectively, p<0.05). Furthermore, an inverse correlation was observed between BMP6 mRNA level and the number of MFPCs in patients with diabetes (r=-0.85, p<0.05). In TK173 cells, BMP6 antagonised the TGF-beta-induced expression of the genes encoding plasminogen activator inhibitor-1 and connective tissue growth factor (70 and 50% reduction, respectively).


CONCLUSIONS
Considering the importance of BMP6 in processes such as angiogenesis and its novel anti-TGF-beta effects, we propose that the excess numbers of BMP6-deficient MFPCs may favour adverse tissue remodelling in patients with diabetes, both numerically and by inappropriate orchestration of their microenvironment.
Nguyen
T Q
TQ
Department of Pathology - H04.312, University Medical Centre, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
Chon
H
H
van Nieuwenhoven
F A
FA
Braam
B
B
Verhaar
M C
MC
Goldschmeding
R
R
D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000172:deficiency / Q000235:genetics*; D018929:Cell Culture Techniques; D055513:Connective Tissue Growth Factor; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology*; D005347:Fibroblasts / Q000166:cytology* / Q000473:pathology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007700:Kinetics; D008233:Lymphotoxin-alpha / Q000494:pharmacology; D032446:Myoblasts / Q000166:cytology*; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012016:Reference Values; D013234:Stem Cells / Q000166:cytology* / Q000473:pathology
C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; C526317:CCN2 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008233:Lymphotoxin-alpha; D017395:Plasminogen Activator Inhibitor 1; D055513:Connective Tissue Growth Factor