https://doi.org/10.4081/ejtm.2025.14289
Tremella fuciformis polysaccharide: enhancing ischemic hypoxic adaptation of mesenchymal stem cells
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: 7 October 2025
Human Placenta-Derived Mesenchymal Stem Cells (HP-MSCs) are recognized for their potential in treating various diseases due to their multidirectional differentiation and immunomodulatory abilities. However, the therapeutic efficacy is often compromised in ischemic and hypoxic environments. Tremella Fuciformis Polysaccharide (TFP), a natural polysaccharide known for its immunomodulatory and anti-inflammatory properties, stands a good chance of overcoming this limitation. Our study investigates whether TFP enhances the therapeutic efficacy of HP-MSCs under ischemic-hypoxic conditions by inhibiting autophagy, with a focus on the role of the ERK signaling pathway. HP-MSCs were cultured under hypoxic conditions to simulate an ischemic environment and TFP was added to investigate its effects on MSC bioactivity, apoptosis, and proliferation. Mechanistic studies were conducted to assess the activation of the ERK signaling pathway and the expression of autophagy-related markers. TFP enhanced HP-MSC bioactivity under hypoxia by reducing apoptosis and promoting proliferation. Mechanistic analysis revealed that TFP enhanced the ability of HP-MSCs to adapt to hypoxic stress by activating the ERK signaling pathway. This activation led to the inhibition of autophagy-related markers, suggesting that TFP plays a protective role in hypoxia-induced cell stress. TFP enhances the therapeutic potential of HP-MSCs in ischemic-hypoxic conditions by inhibiting autophagy through ERK signaling pathway activation. These findings provide a theoretical foundation for the use of TFP in treating lower limb ischemia and highlight its potential to improve treatment protocols and outcomes.
Downloads
1. Han Y, Yang J, Fang J, et al. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Targeted Ther 2022;7:92. DOI: https://doi.org/10.1038/s41392-022-00932-0
2. Yang Y, Peng Y, Li Y, et al. Role of stem cell derivatives in inflammatory diseases. Front Immunol 2023;14:1153901. DOI: https://doi.org/10.3389/fimmu.2023.1153901
3. Ge X, Huang W, Xu X, et al. Production, structure, and bioactivity of polysaccharide isolated from Tremella fuciformis XY. Int J Biol Macromol 2020;148:173-81. DOI: https://doi.org/10.1016/j.ijbiomac.2020.01.021
4. Lee J, Ha SJ, Lee HJ, et al. Protective effect of Tremella fuciformis Berk extract on LPS-induced acute inflammation via inhibition of the NF-κB and MAPK pathways. Food Function 2016;7:3263-72. DOI: https://doi.org/10.1039/C6FO00540C
5. Xie L, Yang K, Liang Y, et al. Tremella fuciformis polysaccharides alleviate induced atopic dermatitis in mice by regulating immune response and gut microbiota. Front Pharmacol 2022;13:944801. DOI: https://doi.org/10.3389/fphar.2022.944801
6. Ma X, Yang M, He Y, et al. A review on the production, structure, bioactivities and applications of Tremella polysaccharides. Int J Immunopathol Pharmacol 2021;35:20587384211000541. DOI: https://doi.org/10.1177/20587384211000541
7. Schwartz LM. Autophagic cell death during development–ancient and mysterious. Front Cell Develop Biol 2021;9:656370. DOI: https://doi.org/10.3389/fcell.2021.656370
8. Xu Y, Yang X. Autophagy and pluripotency: self-eating your way to eternal youth. Trends Cell Biol 2022;32:868-82. DOI: https://doi.org/10.1016/j.tcb.2022.04.001
9. Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer. Nature Rev Molec Cell Biol 2023;24:560-75. DOI: https://doi.org/10.1038/s41580-023-00585-z
10. Łabędź-Masłowska A, Vergori L, Kędracka-Krok S, et al. Mesenchymal stem cell-derived extracellular vesicles exert pro-angiogenic and pro-lymphangiogenic effects in ischemic tissues by transferring various microRNAs and proteins including ITGa5 and NRP1. J Nanobiotechnol 2024;22:60. DOI: https://doi.org/10.1186/s12951-024-02304-y
11. Thanaskody K, Jusop AS, Tye GJ, et al. MSCs vs. iPSCs: Potential in therapeutic applications. Front Cell Develop Biol 2022;10:1005926. DOI: https://doi.org/10.3389/fcell.2022.1005926
12. Al Subayyil A, Basmaeil YS, Alenzi R, Khatlani T. Human Placental Mesenchymal Stem/Stromal cells (pMSCs) inhibit agonist‐induced platelet functions reducing atherosclerosis and thrombosis phenotypes. J Cell Molec Med 2021;25:9268-80. DOI: https://doi.org/10.1111/jcmm.16848
13. Katz MH. Traditional Chinese Medicine to Prevent Type 2 Diabetes—A Difficult Path Forward. JAMA Int Med 2024;184:736. DOI: https://doi.org/10.1001/jamainternmed.2024.1208
14. Xie C, Sun Q, Chen J, et al. Cu–Tremella fuciformis polysaccharide–based tumor microenvironment–responsive injectable gels for cuproptosis-based synergistic osteosarcoma therapy. Int J Biol Macromolec 2024;270:132029. DOI: https://doi.org/10.1016/j.ijbiomac.2024.132029
15. Li X, Su Q, Pan Y. Overcharged lipid metabolism in mechanisms of antitumor by Tremella fuciformis-derived polysaccharide. Int J Oncol 2022;62:11. DOI: https://doi.org/10.3892/ijo.2022.5459
16. Wang J, Zhang S, Wang N, et al. Tremella polysaccharide has potential to retard wheat starch gel system retrogradation and mechanism research. Foods 2023;12:3115. DOI: https://doi.org/10.3390/foods12163115
17. Zhao X, Ma D, Yang B, et al. Research progress of T cell autophagy in autoimmune diseases. Front Immunol 2024;15:1425443. DOI: https://doi.org/10.3389/fimmu.2024.1425443
18. Wang S, Chao X, Jiang X, et al. Loss of acinar cell VMP1 triggers spontaneous pancreatitis in mice. Autophagy 2022;18:1572-82. DOI: https://doi.org/10.1080/15548627.2021.1990672
19. Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nature Rev Molec Cell Biol 2018;19:349-64. DOI: https://doi.org/10.1038/s41580-018-0003-4
20. Kitada M, Koya D. Autophagy in metabolic disease and ageing. Nature Rev Endocrinol 2021;17:647-61. DOI: https://doi.org/10.1038/s41574-021-00551-9
21. Ma Y, Jiao Z, Liu X, et al. Protective effect of adipose-derived stromal cell-secretome attenuate autophagy induced by liver ischemia–reperfusion and partial hepatectomy. Stem Cell Res Ther 2022;13:427. DOI: https://doi.org/10.1186/s13287-022-03109-2
22. Scalabrin M, Engman V, Maccannell A, et al. Temporal analysis of skeletal muscle remodeling post hindlimb ischemia reveals intricate autophagy regulation. Am J Physiol Cell Physiol 2022;323:C1601-10. DOI: https://doi.org/10.1152/ajpcell.00174.2022
23. Kamel R, El Morsy EM, Elsherbiny ME, Nour‐Eldin M. Chrysin promotes angiogenesis in rat hindlimb ischemia: Impact on PI3K/Akt/mTOR signaling pathway and autophagy. Drug Develop Res 2022;83:1226-37. DOI: https://doi.org/10.1002/ddr.21954
24. Surana R, Zheng H, Wang J, et al. Abstract A001: an open label, phase II trial of ERK inhibition alone and in combination with autophagy inhibition in patients with metastatic cancreatic cancer. Cancer Res 2024;84:A001. DOI: https://doi.org/10.1158/1538-7445.PANCREATIC24-A001
25. Stalnecker CA, Grover KR, Edwards AC, et al. Concurrent inhibition of IGF1R and ERK increases pancreatic cancer sensitivity to autophagy inhibitors. Cancer Research 2022;82:586-98. DOI: https://doi.org/10.1158/0008-5472.CAN-21-1443
26. Yu H, Lin Y, Zhong Y, et al. Impaired AT2 to AT1 cell transition in PM2. 5-induced mouse model of chronic obstructive pulmonary disease. Respir Res 2022;23:70. DOI: https://doi.org/10.1186/s12931-022-01996-w
27. Ran J, Yin S, Issa R, et al. Key role of macrophages in the progression of hepatic fibrosis. Hepatol Comm 2025;9:e0602. DOI: https://doi.org/10.1097/HC9.0000000000000602
28. Wang X, He B. Endothelial dysfunction: Molecular mechanisms and clinical implications. Med Comm 2024;5:e651. DOI: https://doi.org/10.1002/mco2.651
CRediT authorship contribution
All authors contributed to the present paper.
How to Cite
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.