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cAMP Agonist Forskolin Disrupts Mitochondrial Metabolism and Induces Senescence in Human Mesenchymal Cells
Qiaoling Wang1, Xiaodong Su2, Rongjia Zhu1
1Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College; Center for Excellence in Tissue Engineering, Chinese Academy of Medical Sciences; Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy (BZ0381), Beijing, People's Republic of China.
Abstract:
Adult-derived mesenchymal stem cells (MSCs) can be used in therapies for the treatment of various diseases. The MSCs derived from aging tissues or long-term MSC cultures could have diminished therapeutic effects compared with MSCs derived from younger tissues, but the underlying mechanism has not been completely established. Dysfunction of energy metabolism is one of the main mechanisms underlying cell senescence. Although cyclic adenosine monophosphate (cAMP) is known to inhibit cell division and proliferation in vitro, its impact on MSC senescence has not been described. In this study, we used forskolin, an adenylate cyclase agonist and cAMP inducer, to disrupt metabolism in human adipose-derived MSCs and investigate the effects of metabolic dysfunction on MSC senescence. Treatment of human MSCs with forskolin resulted in senescence phenotypes, including reduced proliferation, cell-cycle arrest, and enhanced expression of the cell aging markers p16 and p21. Further, the senescent MSCs exhibited increased adipogenesis capacity and decreased osteogenesis capacity as well as a senescence-associated secretory phenotype characterized by increased expression of several inflammatory factors. Forskolin-associated MSC senescence was mainly caused by oxidative stress-induced disruption of mitochondrial metabolism, and the senescent MSCs had high levels of reactive oxygen species and reduced sirtuin gene expression. Lastly, we found that cAMP inhibitor SQ22536 protects MSCs from forskolin-induced senescence and senescence-related inflammatory phenotype. Our results indicate that forskolin can cause senescence of human MSCs through oxidative stress-induced mitochondrial metabolic dysfunction, and thus the results provide a basis for developing strategies for improving the quality and efficacy of cultured MSCs for clinical use.
Insights
Forskolin induces senescence in human mesenchymal stem cells (MSCs) by disrupting mitochondrial metabolism and increasing oxidative stress. This finding offers insights into improving MSC quality for clinical applications.
Area of Science:
- Cell Biology
- Stem Cell Biology
- Metabolic Disease
Background:
- Adult-derived mesenchymal stem cells (MSCs) show therapeutic potential but can diminish with age or prolonged culture.
- Cellular senescence, linked to metabolic dysfunction, is a key factor in reduced MSC efficacy.
- The role of cyclic adenosine monophosphate (cAMP) in MSC senescence remains largely unexplored.
Purpose of the Study:
- To investigate the impact of metabolic disruption, induced by forskolin (a cAMP inducer), on human adipose-derived MSC senescence.
- To elucidate the mechanisms underlying forskolin-induced MSC senescence, focusing on energy metabolism and oxidative stress.
- To evaluate the potential of a cAMP inhibitor to prevent MSC senescence.
Main Methods:
- Human adipose-derived MSCs were treated with forskolin to induce metabolic dysfunction.
- Senescence was assessed by measuring proliferation, cell-cycle arrest, and expression of aging markers (p16, p21).
- Mitochondrial metabolism, oxidative stress (ROS levels), and sirtuin gene expression were analyzed. The effect of cAMP inhibitor SQ22536 was also evaluated.
Main Results:
- Forskolin treatment induced MSC senescence, characterized by reduced proliferation, cell-cycle arrest, and elevated p16/p21 expression.
- Senescent MSCs displayed altered differentiation potential (increased adipogenesis, decreased osteogenesis) and a senescence-associated secretory phenotype (increased inflammatory factors).
- Forskolin-induced senescence was linked to oxidative stress, mitochondrial metabolic dysfunction, high ROS levels, and reduced sirtuin expression. SQ22536 mitigated these effects.
Conclusions:
- Forskolin triggers human MSC senescence via oxidative stress-induced mitochondrial metabolic dysfunction.
- Understanding this mechanism provides a basis for strategies to enhance the quality and therapeutic efficacy of cultured MSCs.
- Targeting cAMP signaling may offer a therapeutic avenue to preserve MSC function in clinical settings.
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