Identification of Three Early Phases of Cell-Fate Determination during Osteogenic and Adipogenic Differentiation by Transcription Factor Dynamics.
Age-related skeletal degeneration in patients with osteoporosis is characterized by decreased bone mass and occurs concomitant with an increase in bone marrow adipocytes. Using microarray expression profiling with high temporal resolution, we identified gene regulatory events in early stages of osteogenic and adipogenic lineage commitment of human mesenchymal stromal cells (hMSCs). Data analysis revealed three distinct phases when cells adopt a committed expression phenotype: initiation of differentiation (0-3 hr, phase I), lineage acquisition (6-24 hr, phase II), and early lineage progression (48-96 hr, phase III). Upstream regulator analysis identified 34 transcription factors (TFs) in phase I with a role in hMSC differentiation. Interestingly, expression levels of identified TFs did not always change and indicate additional post-transcriptional regulatory mechanisms. Functional analysis revealed that forced expression of IRF2 enhances osteogenic differentiation. Thus, IRF2 and other early-responder TFs may control osteogenic cell fate of MSCs and should be considered in mechanistic models that clarify bone-anabolic changes during clinical progression of osteoporosis.
Bone and Calcium Metabolism, Department Internal Medicine, Erasmus MC, Wytemaweg 80, Postbus 2040, 3000 CA Rotterdam, the Netherlands.
Jeroen
J
van de Peppel
Bone and Calcium Metabolism, Department Internal Medicine, Erasmus MC, Wytemaweg 80, Postbus 2040, 3000 CA Rotterdam, the Netherlands.
Tanja
T
Strini
Bone and Calcium Metabolism, Department Internal Medicine, Erasmus MC, Wytemaweg 80, Postbus 2040, 3000 CA Rotterdam, the Netherlands.
Julia
J
Tilburg
Synthetic Systems Biology, University of Amsterdam, 1081 HZ Amsterdam, the Netherlands; Molecular Cell Physiology, VU University Amsterdam, 1081 HZ Amsterdam, the Netherlands; Systems Biology, MCISB, University of Manchester, Manchester M1 7DN, UK.
Hans
H
Westerhoff
Bone and Calcium Metabolism, Department Internal Medicine, Erasmus MC, Wytemaweg 80, Postbus 2040, 3000 CA Rotterdam, the Netherlands; Department of Orthopedic Surgery, Biochemistry & Molecular Biology, and Physiology & Biomedical Engineering, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
Andre J
AJ
van Wijnen
Bone and Calcium Metabolism, Department Internal Medicine, Erasmus MC, Wytemaweg 80, Postbus 2040, 3000 CA Rotterdam, the Netherlands. Electronic address: j.vanleeuwen@erasmusmc.nl.
Johannes P
JP
van Leeuwen
D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D050156:Adipogenesis; D000328:Adult; D002454:Cell Differentiation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
D014157:Transcription Factors
adipocyte; bioinformatics; bone; gene expression profiling; human MSC differentiation; interferon; osteoblast; regenerative medicine; transcription factor