Pharmacological regulation of adult stem cells: chondrogenesis can be induced using a synthetic inhibitor of the retinoic acid receptor.
Conventional methods for regulating the differentiation of stem cells are largely based on the use of biological agents such as growth factors. We hypothesize that stem cell differentiation could be driven by specific synthetic molecules. If true, this would offer the possibility of screening chemical libraries to develop pharmacological agents with improved efficacy. To test our hypothesis, we have determined which, if any, of the nuclear receptor superfamily might be involved in chondrogenesis. We used fluorescence-activated cell sorting, as well as quantitative polymerase chain reaction, to study expression of a range of nuclear receptors in the undifferentiated mesenchymal population and after growth factor-driven differentiation of these cells to chondrocytes. In this way, we identified retinoic acid receptor beta (RAR beta) as a potential pharmacological target. A low molecular weight synthetic inhibitor of the RAR alpha and RAR beta receptors was able to induce chondrogenic differentiation of mesenchymal stem cells derived from osteoarthritis patients, in the absence of serum and growth factors. Furthermore, the pathway is independent of SOX9 upregulation and does not lead to hypertrophy. When mesenchymal cells were seeded on to polyglycolic acid scaffolds and cultured with LE135, there was a dose-dependent formation of cartilage, demonstrated both histologically and by biochemical analysis of the collagen component of the extracellular matrix. These results demonstrate the feasibility of a pharmacological approach to the regulation of stem cell function. Disclosure of potential conflicts of interest is found at the end of this article.
Kafienah
Wael
W
Academic Rheumatology, Department of Clinical Science at North Bristol, University of Bristol, United Kingdom.
Mistry
Sanjay
S
Perry
Mark J
MJ
Politopoulou
Galatia
G
Hollander
Anthony P
AP
D017667:Adipocytes / Q000166:cytology; D000328:Adult; D053687:Adult Stem Cells / Q000166:cytology / Q000187:drug effects*; D000368:Aged; D002358:Cartilage, Articular / Q000166:cytology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology*; D020219:Chondrogenesis / Q000187:drug effects* / Q000235:genetics; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003984:Dibenzazepines / Q000494:pharmacology*; D005260:Female; D006609:High Mobility Group Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D008875:Middle Aged; D010003:Osteoarthritis / Q000473:pathology; D010011:Osteocytes / Q000166:cytology; D034741:RNA, Small Interfering / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000502:physiology; D055758:SOX9 Transcription Factor; D023822:Tissue Engineering / Q000379:methods; D054457:Tissue Scaffolds; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology
D016895:Culture Media, Serum-Free; D003984:Dibenzazepines; D006609:High Mobility Group Proteins; C104182:LE 135; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D014157:Transcription Factors; C082925:retinoic acid receptor beta