Pretreatment of Mesenchymal Stem Cells with Melatonin Improves Their Healing Properties in Animals with Strokes

The transplantation of mesenchymal stem cells or MSCs as they as affectionately known, does indeed benefit patients who have had a stroke. Unfortunately, the benefits of MSC transplantation if is limited by inability of these cells to survive after they are implanted into a low-oxygen environment. When a person suffers from a stroke, a blood vessel that feeds the brain has been blocked, and this blockage results in the death of particular cells in the brain. The affected areas of the brain, however, have been deprived of oxygen, and the transplantation of new cells into these areas can result in the prompt death of the implanted cells.

Fortunately, previous studies have revealed that pretreatment of the implanted cells with the hormone melatonin can increase the survival of MSCs that were implanted into kidneys that suffered oxygen deprivation. Therefore, could melatonin pretreatment also improve MSC survival in the case of strokes?

A new study by Guo-Yuan Yang and his colleagues at the Med-X Research Institute in Shanghai, China has examined the effects of melatonin pretreatment on the survival of MSCs that were implanted into the brains of laboratory animals that suffered a stroke.

In a nutshell, Yang and his colleagues showed that melatonin pretreatment greatly increased survival of cultured MSCs when these cells were subjected to low-oxygen conditions. Then when they went whole hog and transplanted their melatonin-pretreated MSCs into the brains of animals that had suffered a stroke, they once again observed that these cells survived at a substantially higher rate than their untreated counterparts. Melatonin-pretreated MSCs also further reduced bleeds into the brain (infarction) and improved the behavioral outcomes of the laboratory animals.

When Yang’s group examined the molecules secreted by the melatonin-treated MSCs, they discovered that the melatonin-pretreated MSCs made a lot more blood-vessel-promoting proteins (such as vascular endothelial growth factor or VEGF), and nerve cell-promoting molecules. Not surprisingly, the rats implanted with melatonin-pretreated MSCs shows significantly more new blood vessels formed, new neurons formed, and better looking brains in general.

Melatonin treatment increased the levels of two signaling molecules, p-ERK1/2, in MSCs. These particular signaling molecules are linked to higher survival rates. When Yang and his crew blocked melatonin signaling by treating cells with as drug called luzindole, these positive effects were reversed and when another drug called U0126, which prevents ERK from becoming phosphorylated was also applied to the cells, it completely reversed the protective effects of melatonin.

These results show that melatonin improves MSC survival and function. Furthermore, melatonin does this by activating the ERK1/2 signaling pathway. Therefore, mesenchymal cells pretreated by melatonin may represent a viable approach to enhance the beneficial effects of stem cell therapy for strokes, and maybe other conditions too? Well shall see. Stay tuned…..

Stem Cell Therapy Repairs Brain Damage Hours After Stroke Occurs

According to the Center for Disease Control, stroke is a leading cause of death in the United States. Fortunately stroke has been the subject of significant research efforts, but unfortunately, developing treatments that ensure complete recovery for stroke patients is extremely challenging. The challenge increase when more than a few hours have passed between onset of the stroke and administration of treatment.

Thus a new study released in STEM CELLS Translational Medicine has generated more than a little excitement. This study indicates that indicates that endothelial precursor cells (EPCs), which are found in the bone marrow, umbilical cord blood, and rarely in peripheral blood, can make a significant difference for these patients’ recovery. The contribution of EPCs even extends to the later stages of stroke. In animal studies, EPC implantation into the brain after a stroke minimized the initial brain injury and helped repair the stroke damage.

“Previous studies indicated that stem/progenitor cells derived from human umbilical cord blood (hUCB) improved functional recovery in stroke models,” noted Branislava Janic, Ph.D., a member of Henry Ford Health System’s Cellular and Molecular Imaging Laboratory in Detroit and lead author of the study. “We wanted to examine the effect of hUCB-derived AC133+ endothelial progenitor cells (EPCs) on stroke development and resolution in rats.”

Dr. Janic and his team injected EPCs into the brains of rats that had suffered strokes. When they later examined the animals using MRI, they found that the transplanted EPCs had selectively migrated to the injured area, stopped the tissue damage from spreading, initiated regeneration, and affected the time course for stroke resolution. The lesion size in the brain was significantly decreased at a dose of 10 million cells, if the cells were given as early as seven days after the onset of the stroke.

“This led us to conclude that cord blood-derived EPCs can significantly contribute to developing more effective treatments that allow broader time period for intervention, minimize the initial brain injury and help repair the damage in later post-stroke phases,” Dr. Janic said.

“The early signs of stroke are often unrecognized, and many patients cannot take advantage of clot-busting treatments within the required few hours after stroke onset,” said Anthony Atala, M.D., editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. “In this animal study, a combination of stem cells shows promise for healing stroke damage when administered 24 hours after the stroke.”