Gene therapy promotes nerve regeneration

Researchers from the Netherlands Institute for Neuroscience (NIN) and the Leiden University Medical Center (LUMC) have shown that treatment using gene therapy leads to a faster recovery after nerve damage. By combining a surgical repair procedure with gene therapy, the survival of nerve cells and regeneration of nerve fibers over a long distance was stimulated for the first time. The discovery, published in the journal Brain, is an important step towards the development of a new treatment for people with nerve damage.

During birth or following a traffic accident, nerves in the neck can be torn out of the spinal cord. As a result, these patients lose their arm function, and are unable to perform daily activities such as drinking a cup of coffee. Currently, surgical repair is the only available treatment for patients suffering this kind of nerve damage.

"After surgery, nerve fibers have to bridge many centimeters before reaching the muscles and nerve cells from which new fibers need to regenerate are lost in large numbers. Most regenerating nerve fiber do not reach the muscles. The recovery of arm function is therefore disappointing and incomplete," explains researcher Ruben Eggers of the NIN.

Combination of treatments

By combining neurosurgical repair with gene therapy in rats, many of the dying nerve cells can be rescued and nerve fiber growth in the direction of the muscle can be stimulated.

In this study, the researchers used regulatable gene therapy with a growth factor that could be switched on and off by using a widely used antibiotic. "Because we were able to switch off the gene therapy when the growth factor was no longer needed, the regeneration of new nerve fibers towards the muscles was improved considerably," says Ruben Eggers.

A stealth gene switch

To overcome the problem of the immune system recognizing and removing the gene switch, the researchers developed a hidden version, a so-called 'stealth switch'. Professor Joost Verhaagen (NIN) explains: "The stealth gene switch is an important step forward towards the development of gene therapy for nerve damage. The use of a stealth switch improves the gene therapy rendering it even safer."

The gene therapy is not yet ready for use in patients. While the ability to switch off a therapeutic gene is a large step forward, the researchers still found small amounts of the active gene when the switch was turned off. Therefore, further research is needed to optimize this therapy.

Researchers from different part of the world are invited to submit abstract on their unpublished latest research at our upcoming conference Cell Tissue Science 2019 which is focused on the complications and consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology,Technical Advancements in cancer treatment and many more. We as committee members of the conference welcome you to be a part of the conference “ 12th World Congress on Cell & Tissue Science” in Singapore on March 11-12, 2019. 

You can submit your abstract on Session or Track : 02. Gene Therapy

Why haven't cancer cells undergone genetic meltdowns?

Cancer first develops as a single cell going rogue, with mutations that trigger aggressive growth at all costs to the health of the organism. But if cancer cells were accumulating harmful mutations faster than they could be purged, wouldn't the population eventually die out?

How do cancer cells avoid complete genetic meltdown?

Famously isolated from cervical cancer victim Henrietta Lacks in 1951, they became the first immortalized cell line, helped in the development of the polio vaccine, and have become a biotechnology foundational resource for any in vitro drug development or cancer studies.

And they are still providing ample opportunities to further our understanding of cancer.

"In this study, HeLa cells are not used to reveal the process of tumorigenesis but mainly a model for addressing the underlying evolutionary forces, which need to be powerful enough to measure in laboratory settings. We examined variation in growth rate among individual HeLa cells by monitoring clones from a common ancestral HeLa cell population," said corresponding author Xuemei Lu.

They first established a HeLa cell line (E6) derived from an ancestral cell line. When the population size of E6 reached approximately 5 × 104 cells (15~16 divisions), five single-cell clones were generated and established in culture. They team DNA sequenced these clones to catalog the mutations. They focused on copy number variation (CNV) rather than single DNA changes because single-nucleotide mutation rates are too slow to produce significant sequence variation during the short-duration culturing experiments.

"We then estimated the deleterious mutation rate and the average fitness decrease per mutation by performing computer simulations of cell growth," said author Hurng-Yi Wang.

Overall, they found that the main mutations affect the copy number of genes, with an average of 0.29 deleterious events for every cell division. Each of these events reduces fitness 18 percent.

Their results indicate that heterogeneity in cell growth can be generated in a very short period of time in cancer cells and is heritable and genetically determined.

"Our estimates indicate that the HeLa cells experience a 5 percent reduction (0.29 ×0.18 ? 5%) in fitness for every generation. Our observations suggest that human cells that have been cultured for a sufficiently long period still generate deleterious mutations in the form of CNVs at a high rate and with a high intensity. For such systems, a mutational meltdown might be plausible."

For example, when they isolated 39 cells from B8 (a fast-growing clone) and 40 cells from E3 (slow growing clone), and monitored their growth from a single cell for seven days, approximately 23 percent of B8 and 50 percent of E3 cells died out within seven days, due to either damage caused during cell isolation or genetic defects.

Most cell lines with growth rates < 0.6 died within 2 months. In total, only 60 percent of B8 and 27 percent of E3 cells survived for more than two months.

Next, they picked about 20 cells from each of the single cell originated clones from B8 and counted their chromosome numbers.

The chromosomes varied far from the normal human number of 46. They ranged from 38 to 113 chromosomes, with most (72 percent) cells harboring between 55 and 70 chromosomes, indicating that they are triploid. Therefore, despite single-cell origin, the progeny quickly generated aneuploidy within only 20-30 cell divisions, again illustrating frequent cytogenetic change in cancer cells.

Despite the level of mutations occurring, reduction in growth rates, and chromosome numbers no longer representing that of normal humans, cancer cells still find a way to survive.

So how do HeLa cells persist?

"High deleterious mutation rate would raise an impression that the HeLa cell lines may have gone extinct long ago," said Lu.

Their simulation results indicated that although most of the cells accumulated deleterious mutations and were worse than the ancestral cells, there were still 13.1 percent of cells which were mutation-free.

"These mutation-free cells can avoid the population from extinction."

It also explains why, even if chemotherapy treatment successfully killed 90 percent of a cancer cell population, it may still not be enough.

The new study not only advances the understanding of the evolution of HeLa cells, and of tumors in general, but of the cells of multicellular organisms in culture in general. In future work, the scientists want to exploit their cancer cell fitness and growth rate findings to understand how cancer cells can become even more vulnerable to recent breakthroughs with checkpoint inhibitor drugs.

Researchers from different part of the world are invited to submit abstract on their unpublished latest research at our upcoming conference Cell Tissue Science 2019 which is focused on the complications and consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology,Technical Advancements in cancer treatment and many more. We as committee members of the conference welcome you to be a part of the conference “ 12th World Congress on Cell & Tissue Science” in Singapore on March 11-12, 2019. 

You can submit your abstract on Session or Track : 08. Advancement in Cancer Treatments

 

Maternal programming during pregnancy induces long-term postpartum obesity

During normal pregnancy, mothers always gain body weight within a proper range. However, many women worry that extra pounds put on during pregnancy will not be lost after childbirth and, in fact, past studies have shown that excessive gestational weight gain is associated with immediate postpartum weight retention. But in a new study using a mouse model, researchers at University of California San Diego School of Medicine suggest that long-term postpartum weight gain may be due not so much to retained fat as to reprogramming of maternal energy metabolism.

Writing in the January 8 online issue of the International Journal of Obesity, a team of researchers led by senior author Jianhua Shao, MD, PhD, professor in the Department of Pediatrics at UC San Diego School of Medicine, found that pregnant mice fed a high-fat (HF) diet gained significantly more body fat compared to control mice, but quickly lost the added weight after giving birth.

However, even with a normal diet three months after parturition or giving birth, pregnant mice that received a HF diet during pregnancy began gaining more fat again and nine months after delivery weighed two-fold above levels of control mice due to excess fat mass. Notably, the scientists said the metabolism of mice who were fed a HF diet during pregnancy had slowed, measurably reducing their energy expenditure and thus contributing to fatty weight gain.

"Excessive gestational weight gain increases the risk of long-term postpartum obesity," said Shao, "and our study showed that pregnant mice consuming a high fat diet significantly increased white fat cell gain, which is characteristic in humans too.

"But these mice lost that weight gain soon after giving birth, only to become spontaneously obese a few months later. The data demonstrate that excessive gestational weight gain-induced postpartum obesity is not simply an extension of pregnancy-induced fat gain or fat retention, but rather a fundamental change in maternal metabolism that results in less energy expended and more weight added as the result."

Specifically, Shao and colleagues found that while levels of blood estrogen in mice fed HF during pregnancy and three groups of control mice were similar after giving birth, there was a significant decrease in estrogen signaling in both white and brown adipose tissues in the HF fed group. Their study suggests that the reduction of estrogen signaling gradually develops after pregnancy and giving birth due to the slow adipocyte renewal process. Given that estrogen plays an important role in fat development and energy metabolism, the impairment of estrogen signaling within fat may provide a mechanism for excessive weight gain-induced, long-term postpartum obesity.

The authors underscored that their findings are based on studies of mice and will need to be verified in humans. But if they are, said Shao, it "will lead us to define a new cause of obesity in women after pregnancy and will reveal a new vulnerable window for reprogramming of energy metabolism during adult life."

The authors said their findings, if confirmed in humans, could provide an explanation for how women have overtaken men in the obesity epidemic. After similar rising rates of obesity for more than a decade, a 2015 report by the Centers for Disease Control and Prevention found that women had surpassed men in terms of obesity, with 38 percent of adult women in the United States deemed obese compared to 34 percent of men. More recent statistics place those percentages even higher at 41 and 38, respectively. Clinical data have demonstrated that obesity has significant health risks to the mother in later life, including cardiovascular disease and diabetes.

Researchers from different part of the world are invited to submit abstract on their unpublished latest research at our upcoming conference Cell Tissue Science 2019 which is focused on the complications and consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology,Technical Advancements in cancer treatment and many more. We as committee members of the conference welcome you to be a part of the conference “ 12th World Congress on Cell & Tissue Science” in Singapore on March 11-12, 2019. 

You can submit your abstract on Session or Track : 09. Stem Cells and its Applications

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Stem cell-derived neurons stop seizures and improve cognitive function

About 3.4 million Americans, or 1.2 percent of the population, have active epilepsy. Although the majority respond to medication, between 20 and 40 percent of patients with epilepsy continue to have seizures even after trying multiple anti-seizure drugs. Even when the drugs do work, people may develop cognitive and memory problems and depression, likely from the combination of the underlying seizure disorder and the drugs to treat it.

Seizures are caused when the excitatory neurons in the brain fire too much and inhibitory neurons -- the ones that tell the excitatory neurons to stop firing -- aren't as abundant or aren't operating at their optimal level. The main inhibitory neurotransmitter in the brain is called GABA, short for gamma-Aminobutyric acid.

Over the last decade, scientists have learned how to create induced pluripotent stem cells from ordinary adult cells, like a skin cell. These stem cells can then be coaxed to become virtually any type of cells in the body, including neurons that use GABA, called GABAergic interneurons.

"What we did is transplant human induced pluripotent stem cell-derived GABAergic progenitor cells into the hippocampus in an animal model of early temporal lobe epilepsy," Ashok K. Shetty, Professor, Department of Molecular and Cellular Medicine, Texas A&M College of Medicine and Associate Director of the Institute for Regenerative Medicine said. The hippocampus is a region in the brain where seizures originate in temporal lobe epilepsy, which is also important for learning, memory and mood. "It worked very well to suppress seizures and even to improve cognitive and mood function in the chronic phase of epilepsy."

Further testing showed that these transplanted human neurons formed synapses, or connections, with the host excitatory neurons. "They were also positive for GABA and other markers of specialized subclasses of inhibitory interneurons, which was the goal," Shetty said. "Another fascinating aspect of this study is that transplanted human GABAergic neurons were found to be directly involved in controlling seizures, as silencing the transplanted GABAergic neurons resulted in an increased number of seizures."

"This publication by Dr. Shetty and his colleagues is a major step forward in treating otherwise incurable diseases of the brain," said Darwin J. Prockop, MD, PhD, the Stearman Chair in Genomic Medicine, Director of the Texas A&M Institute for Regenerative Medicine and Professor at the Texas A&M College of Medicine. "One important aspect of the work is that the same cells can be obtained from a patient." This type of process, called autologous transplant, is patient specific, meaning that there would be no risk of rejection of the new neurons, and the person wouldn't need anti-rejection medication.

"We will need to make sure that we're doing more good than harm," Shetty said. "Going forward, we need to make sure that all of the cells transplanted have turned into neurons, because putting undifferentiated pluripotent stem cells into the body could lead to tumors and other problems."

The development of epilepsy often happens after a head injury, which is why the Department of Defense is interested in funding the development of better treatment and prevention options.

"A great deal of research is required before patients can be safely treated," Prockop said. "But this publication shows a way in which patients can someday be treated with their own cells for the devastating effects of epilepsy but perhaps also other diseases such as Parkinsonism and Alzheimer's disease."

Shetty cautioned that these tests were early interventions after the initial brain injury induced by status epilepticus, which is a state of continuous seizures lasting more than five minutes in humans. The next step is to see if similar transplants would work for cases of chronic epilepsy, particularly drug-resistant epilepsy. "Currently, there is no effective treatment for drug-resistant epilepsy accompanying with depression, memory problems, and a death rate five to 10 times that of the general population," he said. "Our results suggest that induced pluripotent stem cell-derived GABAergic cell therapy has the promise for providing a long-lasting seizure control and relieving co-morbidities associated with epilepsy."

We welcome researchers from different part of the to submit abstract on their latest research at our upcoming conference Cell Tissue Science 2019 which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology,Technical Advancements in cancer treatmentand many more.We welcome you to the our upcoming conference “ 12th World Congress on Cell & Tissue Science” . 

You can submit your abstract on Session or Track : 09. Stem Cells Biology