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Luchetti F, Carloni S, Nasoni MG, Reiter RJ, Balduini W. Melatonin, tunneling nanotubes, mesenchymal cells, and tissue regeneration. Neural Regen Res. 2023;18(4):760-762. doi:10.4103/1673-5374.353480



Mesenchymal stem cells (MSCs) originate in human tissues and organs and have become an alternative cell source in regenerative therapy. Clinical trials are exploring the use of MSCs in diseases such as osteoarthritis, wound healing, degenerative diseases, and autoimmune conditions.  This review explores how and if melatonin can be used to help preserve MSCs' survival and function after they have been transplanted into the recipient.


Our comments/takeaways from the article

This is an area of melatonin research we will be monitoring with excitement. As the incidences of chronic diseases continue to rise, the need to effectively manage the diseases and improve the quality of life for those living with the diseases is of great interest. While it is too soon to provide clinical application, melatonin may be a plausible adjuvant to MSC therapy due to its mitochondria-regulating properties. 


Article Summary


Mesenchymal stem cells (MSCs) are being explored in regenerative medicine. However, when these cells are transplanted, they lose some of the multipotency and immunomodulatory properties or die after they are injected into the damaged tissue.  This has led to a need to develop strategies to improve their efficacy.


Melatonin, as a mitochondrial regulator, has properties that may help improve MSC therapy.  The mitochondria produce melatonin to optimize membrane potential and control oxidative stress. Importantly, melatonin binds to MT1 receptors on the outer membrane of the mitochondria, inhibiting apoptosis. Additionally, melatonin is essential for autophagy, while also serving as an antioxidant and anti-inflammatory agent. 


It is reported that using melatonin to treat MSCs (ex vivo):

  • reduces oxidative stress

  • reduces senescence

  • prevents membrane depolarization

  • likely modulates autophagy


Of the articles explored to conduct this review, the authors state that melatonin has the potential to enhance MSCs in myocardial infarction, chronic kidney disease, hindlimb ischemia, and focal cerebral ischemia by:

  • upregulating cellular prion protein, increasing the regeneration potential

  • preventing apoptosis after transplantation

  • increasing cell proliferation and survival rate


Further, one study used melatonin on hippocampal HT22 neuronal cells that were deprived of oxygen and glucose.  Melatonin improved cell survival and prevented mitochondrial dysfunction.  The authors state, “...the most novel and important finding that emerged from this study was the observation that, besides preserving mitochondrial function, melatonin also promoted the formation of TNTs and the transfer of mitochondria between cells through the connecting tubules.” TNTs, tunneling nanotubes, allow for direct communication between distant cells sharing cytoplasm, macromolecules, and organelles, such as the mitochondria.  This sharing of information allows for more efficient response to challenges such as tissue repair.


Finally, melatonin may preserve mitochondria function and cell viability by impacting sirtuins, which aid in the prevention of cellular senescence and age-associated diseases. Notably, melatonin is a stimulator of Sirtuin 3, which can reduce oxidative stress.


While melatonin may have the potential for MSCs therapy, this research is in its infancy stage.  Additional research is needed to determine the effective dose and possible limitations melatonin may have for this non-pharmaceutical approach in regenerative medicine.


Article review completed by Kim Ross, DCN

Content reviewed by Deanna Minich, PhD

November 21, 2022

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