Identification of Three Early Phases of Cell-Fate Determination during Osteogenic and Adipogenic Differentiation by Transcription Factor Dynamics

Jeroen van de Peppel, Tanja Strini, Julia Tilburg, Hans Westerhoff, Andre J. van Wijnen, Johannes P van Leeuwen

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)947-960
Number of pages14
JournalStem cell reports
Volume8
Issue number4
DOIs
Publication statusPublished - 11 Apr 2017

Funding

The authors thank Marijke Schreuders-Koedam and Bianca Boers-Sijmons for technical assistance. This work was supported by the Dutch Institute for Regenerative medicine (NIRM: grant no. FES0908), Erasmus MC Stem Cell and Regenerative Medicine Institute, and Erasmus Medical Center (EMC-MM-01-39-02) as well as NIH grant R01 AR049069 (A.J.v.W.). We also acknowledge the generous philanthropic support of William and Karen Eby, as well as the charitable foundation in their names. H.W. is supported by Synpol, EU-FP7 (KBBE.2012.3.4–02 #311815); Corbel, EU-H2020 (INFRADEV-4-2014-2015 #654248); Epipredict, EU-H2020; MSCA-ITN-2014-ETN, Marie Skłodowska-Curie Innovative Training Networks (ITN-ETN) (#642691), by the Netherlands Organization for Scientific Research (NWO) in the integrated program of WOTRO (W01.65.324.00/project 4) Science for Global Development, and by BBSRC China (BB/J020060/1).

FundersFunder number
BBSRC ChinaBB/J020060/1
Dutch Institute for Regenerative medicine
EU-H2020MSCA-ITN-2014-ETN
Erasmus MC Stem Cell and Regenerative Medicine Institute
Marie Skłodowska-Curie Innovative Training Networks
NIRMFES0908
WOTRO
National Institutes of HealthR01 AR049069
Horizon 2020 Framework Programme642691, 654248
Erasmus Medisch CentrumEMC-MM-01-39-02
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Seventh Framework Programme311815

    Keywords

    • adipocyte
    • bioinformatics
    • bone
    • gene expression profiling
    • human MSC differentiation
    • interferon
    • osteoblast
    • regenerative medicine
    • transcription factor

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