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Updated: Sep 28, 2025

Accessing the Cytotoxicity and Cell Response to Biomaterials
Published on: July 8, 2021
ROR2 Downregulation Activates the MSX2/NSUN2/p21 Regulatory Axis and Promotes Dental Pulp Stem Cell Senescence
Xin He1, Zhan Yang2, Xiao-Yang Chu3
1Department of Orthodontics, Beijing Stomatological Hospital, Capital Medical University School of Stomatology, Capital Medical University, Beijing, People's Republic of China.
Abstract:
Cellular senescence severely limits the research and the application of dental pulp stem cells (DPSCs). A previous study conducted by our research group revealed a close implication of ROR2 in DPSC senescence, although the mechanism underlying the regulation of ROR2 in DPSCs remains poorly understood so far. In the present study, it was revealed that the expression of the ROR2-interacting transcription factor MSX2 was increased in aging DPSCs. It was demonstrated that the depletion of MSX2 inhibits the senescence of DPSCs and restores their self-renewal capacity, and the simultaneous overexpression of ROR2 enhanced this effect. Moreover, MSX2 knockdown suppressed the transcription of NOP2/Sun domain family member 2 (NSUN2), which regulates the expression of p21 by binding to and causing the 5-methylcytidine methylation of the 3'- untranslated region of p21 mRNA. Interestingly, ROR2 downregulation elevated the levels of MSX2 protein, and not the MSX2 mRNA expression, by reducing the phosphorylation level of MSX2 and inhibiting the RNF34-mediated MSX2 ubiquitination degradation. The results of the present study demonstrated the vital role of the ROR2/MSX2/NSUN2 axis in the regulation of DPSC senescence, thereby revealing a potential target for antagonizing DPSC aging.
Insights
Cellular senescence in dental pulp stem cells (DPSCs) is linked to ROR2 and MSX2. Targeting the ROR2/MSX2/NSUN2 pathway can inhibit DPSC aging and restore self-renewal capacity.
Area of Science:
- Stem cell biology
- Molecular and cellular biology
- Regenerative medicine
Background:
- Cellular senescence limits dental pulp stem cell (DPSC) research and applications.
- ROR2 is implicated in DPSC senescence, but the regulatory mechanism is unclear.
Purpose of the Study:
- To elucidate the mechanism of ROR2 regulation in DPSC senescence.
- To identify potential targets for antagonizing DPSC aging.
Main Methods:
- Investigated MSX2 expression in aging DPSCs.
- Performed MSX2 depletion and ROR2 overexpression experiments.
- Analyzed the ROR2/MSX2/NSUN2/p21 axis in DPSC senescence.
Main Results:
- MSX2 expression increased in aging DPSCs.
- MSX2 depletion inhibited DPSC senescence and restored self-renewal.
- The ROR2/MSX2/NSUN2 axis was identified as a key regulator of DPSC aging.
- ROR2 downregulation affected MSX2 protein levels by altering phosphorylation and ubiquitination.
Conclusions:
- The ROR2/MSX2/NSUN2 axis plays a vital role in regulating DPSC senescence.
- This pathway represents a potential therapeutic target for combating DPSC aging.
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