Resveratrol targeting Smad4 via a concentration-dependent biphasic effect regulates stem cells-mediated regeneration
Ziqing Zhou1, Shaoming Wu1, Xiaoran Zhang1
1National Demonstration Center for Experimental Basic Medical Education, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Innovation Research Center, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Experimental and Molecular Pathology
|February 15, 2026
Summary
Resveratrol (RSV) exhibits a dual effect on planarian regeneration. Low concentrations promote stem cell proliferation and differentiation, while high concentrations inhibit differentiation, impacting stem cell fates.
Area of Science:
- Stem cell biology
- Regenerative medicine
- Nutraceutical research
Background:
- Resveratrol (RSV) is a widely used nutraceutical with known human health benefits.
- Its effects on stemness and regeneration are not well understood.
- Evidence for its anti-tumor properties is limited.
Purpose of the Study:
- To investigate the impact of varying Resveratrol concentrations on planarian blastema regeneration.
- To elucidate the underlying molecular mechanisms of RSV's effects on stem cells.
- To explore RSV's influence on stem cell proliferation and differentiation.
Main Methods:
- High-throughput RNA sequencing
- RNA interference assays
- Quantitative real-time PCR (RT-qPCR)
- Whole-mount in situ hybridization
- Planarian model organism (Dugesia japonica)
Main Results:
- Resveratrol demonstrated a biphasic effect: 5 μM promoted regeneration, while 50 μM inhibited it.
- Smad4 was identified as a key mediator, with its inhibition worsening regenerative deficits at low RSV concentrations.
- PiwiA expression increased with both RSV concentrations, particularly at low concentrations.
- High-concentration RSV suppressed the late stem cell marker Agat1.
- Low-concentration RSV enhanced stem cell proliferation and differentiation; high-concentration RSV inhibited differentiation.
Conclusions:
- Resveratrol concentration critically dictates stem cell differentiation fates in vivo.
- Low-concentration RSV promotes both stem cell proliferation and differentiation.
- High-concentration RSV inhibits stem cell differentiation independently of Smad4.
- Findings provide a scientific basis for the rational application of Resveratrol.
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