Tag: stem cells

Categories : Cancer Immune SystemTags :

Surprising Mechanism of Action Discovered for Stem Cell Drugs

On By ModernMedia
Two cytotoxic T cells (red) attacking an oral squamous cancer cell. Photo by National Cancer Institute on Unsplash

A new study revealed surprising insights into how specialised drugs that regenerate immune cells lost to chemotherapy actually work. 

In cancer patients following chemotherapy, there is a decrease in immune cells because chemotherapy also impacts the stem cells in bone marrow, which were meant to develop into new immune cells. This means that the immune system is then left short of immune cells to fight new infections.

Certain drugs exist, such as plerixafor, that can stimulate the release of stem cells from the bone marrow into the blood stream, so that they can be harvested and then reintroduced into the patients after treatment. These stem cells develop into new immune cells, bolstering the immune system. However, there was a lack of detailed knowledge of how these drugs actually worked.

Now, a study conducted in mice by researchers at the University of Copenhagen demonstrates how the medicine works at the cell level—and, surprisingly, how plerixafor, one of the two applied and tested drugs, is more effective than the other, despite the fact that the other drug, on paper, appears to be the most effective of the two. This discovery may not just help improve stem cell transplantation; it may also lead to improved drugs in the future.

“We have tested two drugs for stem cell transplantation which appear to have the same effect. What they do is block a receptor, causing the bone marrow to release stem cells into the blood. What the new study shows, though, is that they do not just block the receptor; one of the two drugs also affects other signaling pathways in the cell. And in short, that makes it more effective than the other of the two drugs,” explained PhD student Astrid Sissel Jørgensen from the Department of Biomedical Sciences at the University of Copenhagen.

“We used to believe that all we had to do was block the receptor, and that the two drugs had the same effect. It now appears that there is more to it,” she said.

The drugs tested by the researchers mobilise stem cells by acting as CXCR4 receptor antagonists. There are several drugs that target this receptor, including drugs inhibiting HIV replication.

“The drugs not only block the receptor’s normal signaling. One of the two drugs we have tested also affect some of the other cell pathways and even make the receptor withdraw into the cell and disappear from the surface,” explained corresponding author Professor Mette Rosenkilde. The study results revealed that one of the two drugs makes the bone marrow release more stem cells into the blood.

These findings on how the drugs affect cell pathways differently is also known as biased signalling. Mechanisms like these are what make the one drug more effective in practice than on paper, and they challenge the current view of these drugs.

“The results of our study directly influence our view of drugs used for stem cell transplantation. In the long term, though, it may also affect our view of future drugs, and how new drugs should be designed to have the best possible effect, both in connection with stem cell mobilisation, but also for treating HIV infections, where this particular receptor also plays a main role,” said Prof Rosenkilde.

Source: Medical Xpress

Journal information: Astrid S. Jørgensen et al, Biased action of the CXCR4-targeting drug plerixafor is essential for its superior hematopoietic stem cell mobilization, Communications Biology (2021). DOI: 10.1038/s42003-021-02070-9

Categories : Skeletal SystemTags :

Fat Cells Tapped for Spinal Fusion

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Photo by cottonbro from Pexels

Researchers at Johns Hopkins Medicine have come up with a method that uses adipose cells, better known as fat, as a practical and plentiful source of stem cells for use in spinal fusion surgeries.

Spinal fusion ‘welds’ two or more vertebrae together so that they heal into a single, solid bone. Unfortunately, the surgery — using bone taken from other parts of the patient’s body — fails in up to a fifth of procedures. Stem cells, harvested from a patient’s marrow and allowed to mature into bone cells, can improve the outcome of spinal fusions. However, the aspiration method for getting stem cells out of the marrow carries an infection risk and often is painful.

In a study published in the journal Spine, researchers sought to try out adipose cells rather than bone marrow as a source for the stem cells.

Performing spinal fusion procedures in rats, the researchers found that freshly isolated stem cells from fat worked just as well as the more commonly used bone marrow stem cells. The researchers say this suggests the technique could be a candidate for human clinical trials.

“Bone marrow stem cells are isolated in human patients from the hip,” said Christina Holmes, PhD, a former Johns Hopkins Medicine postdoctoral fellow now at Florida State University. “But using a huge needle to take out bone marrow is a painful procedure, and we can only get a limited number of cells, so we’ve found an alternative source by using stem cells from fat.”

Alexander Perdomo-Pantoja, MD, a postdoctoral fellow at the Johns Hopkins University School of Medicine, said spinal fusion procedures are used to treat many different conditions.

“Spinal fusions are used for anything that causes spinal instability, which usually produces significant mechanical pain,” he says. “You see it frequently when we get older as the intervertebral discs, ligaments and muscles in the spine deteriorate. But these procedures can also be used to treat instability when it is caused by tumors, fractures, deformities or trauma.”

The researchers isolated stem cells from fat and bone marrow, and implanted them into rat spines. For the adipose-derived stem cells, the researchers used freshly isolated cells to see if they could speed up and simplify the procedure.

Stem cells are currently sourced either from bone marrow or fat and are often grown in a lab culture to mature them enough for spinal fusion. During culturing, there is a risk of contamination or transformation into unusable bone. Holmes said that freshly isolating cells avoids these problems, along with reducing labour and material costs.

While stem cells from fat are commonly used in cosmetic procedures, they are not often used in spinal fusions, she adds.

“We feel that fat cells are a logical alternative to bone marrow cells because most patients have an adequate supply of fat cells,” Tsaid imothy Witham, MD, director of the Johns Hopkins Neurosurgery Spinal Fusion Laboratory. ”Fat also is much more accessible during surgery and can be harvested with less stem cell death than bone marrow. Spinal fusion is a very common procedure, and we feel this approach could be applied across a wide cohort of spinal fusion patients.”

The researchers found significantly more bone formation and blood supply in the fresh adipose-derived stem cells compared with what they saw in previous studies with cultured cells from both fat and bone marrow.

The next step for Witham and his team is identifying which cells are the most advantageous for spinal fusions and then characterising them.

Source: John Hopkins University

Journal information: Alexander Perdomo-Pantoja et al. Comparison of Freshly Isolated Adipose Tissue-derived Stromal Vascular Fraction and Bone Marrow Cells in a Posterolateral Lumbar Spinal Fusion Model, Spine (2020). DOI: 10.1097/BRS.0000000000003709

Categories : Ageing NeurologyTags :

Jump-Starting Neural Stem Cells in Aged Brains

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As we age, neural stem cells lose the ability to divide and create new neurons, resulting in a decline in memory. Now, research led by Sebastian Jessberger, a professor at the Brain Research Institute of the University of Zurich, explains why this happens.

The new neurons are used all over the brain, including the hippocampus which is responsible for memory. Declines here from age and Alzheimer’s mean fewer neurons are produced here, impacting memory functions.

“As we get older, stem cells throughout the body gradually lose their ability to proliferate. Using genetic engineering and cutting-edge microscope technology, we were able to identify a mechanism that is associated with this process,” explained doctoral candidate and first author Khadeesh bin Imtiaz. The results were published in the journal Cell Stem Cell.

The study used a mouse model to show that as organisms age, neurons’ ability to divide becomes impaired. Protein structures ensure that accumulated harmful proteins are laid out unequally among the two daughter neurons, important for the longevity of neurons. As the neurons age, the amount of nucleic proteins changes, resulting in impaired distribution of proteins, reducing the number of newly generated neurons in the brains of older mice.

The researchers identified a nuclear protein called lamin B1, levels of which decrease as people age. When lamin B1 was increased in aged mice, there was an improvement in stem cell division and the number of neurons increased.

The study was part of wider research into ageing and stem cells. “While our study was limited to brain stem cells, similar mechanisms are likely to play a key role when it comes to the ageing process of other stem cells,” said Prof Jessberger.

The latest findings represent an important step in understanding how brain stem cells change with age. “We now know that we can reactivate aging stem cells in the brain. Our hope is that these findings will one day help increase levels of neurogenesis, for example in older people or those suffering from degenerative diseases such as Alzheimer’s. Even if this may still be many years in the future,” concluded Prof Jessberger.

Source: Medical Xpress

Journal information: Cell Stem Cell, DOI: 10.1016/j.stem.2021.01.015