Category

News

Home / News
News

Findings could lead to new therapies for cancer, heart abnormalities — ScienceDaily

Look deep inside our cells, and you’ll find that each has an identical genome -a complete set of genes that provides the instructions for our cells’ form and function.

But if each blueprint is identical, why does an eye cell look and act differently than a skin cell or brain cell? How does a stem cell — the raw material with which our organ and tissue cells are made — know what to become?

In a study published July 8, University of Colorado Boulder researchers come one step closer to answering that fundamental question, concluding that the molecular messenger RNA (ribonucleic acid) plays an indispensable role in cell differentiation, serving as a bridge between our genes and the so-called “epigenetic” machinery that turns them on and off.

When that bridge is missing or flawed, the researchers report in the journal Nature Genetics, a stem cell on the path to becoming a heart cell never learns how to beat.

The paper comes at a time when pharmaceutical companies are taking unprecedented interest in RNA. And, while the research is young, it could ultimately inform development of new RNA-targeted therapies, from cancer treatments to therapies for cardiac abnormalities.

“All genes are not expressed all the time in all cells. Instead, each tissue type has its own epigenetic program that determines which genes get turned on or off at any moment,” said co-senior author Thomas Cech, a Nobel laureate and distinguished professor of biochemistry. “We determined in great detail that RNA is a master regulator of this epigenetic silencing and that in the absence of RNA, this system cannot work. It is critical for life.”

Scientists have known for decades that while each cell has identical genes, cells in different organs and tissues express them differently. Epigenetics, or the machinery that switches genes on or off, makes this possible.

But just how that machinery works has remained unclear.

In 2006, John Rinn, now a professor of biochemistry at CU Boulder and co-senior-author on the new paper, proposed for the first time that RNA — the oft-overlooked sibling of DNA (deoxyribonucleic acid) — might be key.

In a landmark paper in Cell, Rinn showed that inside the nucleus, RNA attaches itself to a folded cluster of proteins called polycomb repressive complex (PRC2), which is believed to regulate gene expression. Numerous other studies have since found the same and added that different RNAs also bind to different protein complexes.

The hotly debated question: Does this actually matter in determining a cell’s fate?

No fewer than 502 papers have been published since. Some determined RNA is key in epigenetics; others dismissed its role as tangential at best.

So, in 2015, Yicheng Long, a biochemist and postdoctoral researcher in Cech’s lab, set out to ask the question again using the latest available tools. After a chance meeting in a breakroom at the BioFrontiers Institute where both their labs are housed, Long bumped into Taeyoung Hwang, a computational biologist in Rinn’s lab.

A unique partnership was born.

“We were able to use data science approaches and high-powered computing to understand molecular patterns and evaluate RNA’s role in a novel, quantitative way,” said Hwang, who along with Long is co-first-author on the new paper.

In the lab, the team then used a simple enzyme to remove all RNA in cells to understand whether the epigenetic machinery still found its way to DNA to silence genes. The answer was ‘no.’

“RNA seemed to be playing the role of air traffic controller, guiding the plane — or protein complex — to the right spot on the DNA to land and silence genes,” said Long.

For a third step, they used the gene-editing technology known as CRISPR to develop a line of stem cells destined to become human heart muscle cells but in which the protein complex, PRC2, was incapable of binding to RNA. In essence, the plane couldn’t connect with air-traffic control and lost its way, and the process fell apart.

By day 7, the normal stem cells had begun to look and act like heart cells. But the mutant cells didn’t beat. Notably, when normal PRC2 was restored, they began to behave more normally.

“We can now say, unequivocally, that RNA is critical in this process of cell differentiation,” said Long.

Previous research has already shown that genetic mutations in humans that disrupt RNA’s ability to bind to these proteins boost risk of certain cancers and fetal heart abnormalities. Ultimately, the researchers envision a day when RNA-targeted therapies could be used to address such problems.

“These findings will set a new scientific stage showing an inextricable link between epigenetics and RNA biology,” said Rinn. “They could have broad implications for understanding, and addressing, human disease going forward.”

Source link

News

New clues from fruit flies about the critical role of sex hormones in stem cell control — ScienceDaily

In one of the first studies addressing the role of sex hormones’ impact on stem cells in the gut, scientists outline new insights showing how a steroidal sex hormone, that is structurally and functionally similar to human steroid hormones, drastically alters the way intestinal stem cells behave, ultimately affecting the overarching structure and function of this critical organ. The authors found that ecdysone, a steroid hormone produced by fruit flies, stimulates intestinal stem cell growth and causes the gut of the female fruit fly to grow in size, and induces other critical changes. The study also provides a mechanism to account for sex-specific roles for intestinal stem cells in normal gut function. Moreover, the research presents evidence that gut hormones may accelerate tumor development. The findings, reported jointly by Huntsman Cancer Institute (HCI) at the University of Utah (U of U) and the German Cancer Research Center (DKFZ), are published today in the journal Nature.

Bruce Edgar, PhD, a stem cell biologist at HCI and professor of oncological sciences at the U of U, together with Aurelio Teleman, PhD, division head at DKFZ and professor at Heidelberg University jointly led the work. They asked whether sex hormones affect intestinal stem cells’ ability to multiply and contribute to gut growth. “My lab and many others around the world have studied the Drosophila gut for some time to better understand how stem cells are regulated,” says Edgar. “We knew that male and female fruit flies exhibited differences in their intestine — for example, the female’s intestine is larger than the male’s, and females develop intestinal tumors much more readily than males — but we didn’t know why.” This study adds significant insights into these differences, and how they arise.

The Edgar and Teleman teams found that ecdysone, a sex-specific hormone, can drastically alter the growth properties of stem cells in an organ that, remarkably, is not directly involved in reproduction. They found that these changes affect the structure and function of the entire organ. They discovered that subjecting male flies to ecdysone caused their otherwise slow dividing stem cells to divide as fast as in females, leading to intestinal growth in males as well. This suggests that the limiting difference between the division of stem cells in male and female flies is the circulating levels of the hormone.

This process confers both advantages and disadvantages to the female fruit fly during the course of its life. Initially, more ecdysone in females helps with the evolutionarily critical processes of reproduction. It promotes gut enlargement, facilitating nutrient absorption, which helps the fly lay more eggs. But later in life, the ecdysone hormone, produced by the ovaries, eventually causes gut disfunction that can shorten the lifespan in female fruit flies by creating an environment that favors tumor growth. While humans don’t produce ecdysone, they do have related steroid hormones such as estrogen, progesterone and testosterone, which have similar mechanisms of action.

The experimental work on this study was performed primarily by Sara Ahmed, a joint PhD student between the Edgar and Teleman labs at the Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) and the DKFZ. Ahmed designed experiments utilizing various genetic tools to switch genes on and off in different cell types in the fly’s intestine and in its ovaries, which produce ecdysone. “Our study provides conclusive evidence that sex hormones alter the behavior of non-sex organs like the intestine,” says Ahmed. She further speculates that long-term implications of this research may include exploration of new paths to treating human cancers.

According to the researchers, understanding whether a similar stem cell-hormone relationship operates in human organs will require further studies. They plan to explore this in the future. In addition to the critical role played by sex hormones in intestinal stem cell behavior, the authors believe this study in Drosophila potentially unveils a new mechanism that may play out in human physiology and pathology. Insights from this study add to a growing body of work showing that the incidence cancers of non-reproductive organs, including colon and gastric cancers, are different in males and females.

This study was supported by the National Institutes of Health including the National Cancer Institute P30 CA01420114, the National Institute of General Medical Sciences R01 124434, the European Research Council AdG268515, DKFZ, and Huntsman Cancer Foundation.

Story Source:

Materials provided by Huntsman Cancer Institute. Note: Content may be edited for style and length.

Source link

News

A method that involves infecting liver cells with mosquito-bred parasites could improve the study of malaria in India — ScienceDaily

A new approach could illuminate a critical stage in the life cycle of one of the most common malaria parasites. The approach was developed by scientists at Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS) in Japan and published in the Malaria Journal.

“The Plasmodium vivax malaria parasite can stay dormant in a person’s liver cells up to years following infection, leading to clinical relapses once the parasite is reactivated,” says Kouichi Hasegawa, an iCeMS stem cell biologist and one of the study’s corresponding authors.

P. vivax is responsible for around 7.5 million malaria cases worldwide, about half of which are in India. Currently, there is only one licensed drug to treat the liver stage of the parasite’s life cycle, but it has many side effects and cannot be used in pregnant women and infants. The liver stage is also difficult to study in the lab. For example, scientists have struggled to recreate high infection rates in cultured liver cells.

Hasegawa and his colleagues in Japan, India and Switzerland developed a successful system for breeding mature malaria parasites, culturing human liver cells, and infecting the cells with P. vivax. While it doesn’t solve the high infection rate problem, the system is providing new, localized insight into the parasite’s liver stage.

“Our study provides a proof-of-concept for detecting P. vivax infection in liver cells and provides the first characterization of this infectious stage that we know of in an endemic region in India, home to the highest burden of vivax malaria worldwide,” says Hasegawa.

The researchers bred Anopheles stephensi mosquitos in an insectarium in India. Female mosquitos were fed with blood specifically from Indian patients with P. vivax infection.

Two weeks later, mature sporozoites, the infective stage of the malaria parasite, were extracted from the mosquitos’ salivary glands and added to liver cells cultured in a petri dish.

The scientists tested different types of cultured liver cells to try to find cells that would be infected by lots of parasites like in the human body. Researchers have already tried using cells taken liver biopsies and of various liver cancer cell lines. So far, none have led to large infections.

Hasegawa and his colleagues tried using three types of stem cells that were turned into liver cells in the lab. Notably, they took blood cells from malaria-infected patients, coaxed them into pluripotent stem cells, and then guided those to become liver cells. The researchers wondered if these cells would be genetically more susceptible to malaria infection. However, the cells were only mildly infected when exposed to the parasite sporozoites.

A low infection rate means the liver cells cannot be used for testing many different anti-malaria compounds at once. But the researchers found the cells could test if a specific anti-malaria compound would work for a specific patient’s infection. This could improve individualized treatment for patients.

The scientists were also able to study one of the many aspects of parasite liver infection. They observed the malaria protein UIS4 interacting with the human protein LC3, which protected the parasite from destruction. This demonstrates their approach can be used to further investigate this important stage in the P. vivax life cycle.

Story Source:

Materials provided by Kyoto University. Note: Content may be edited for style and length.

Source link

News

What the embryo can teach us about cell reprogramming — ScienceDaily

Cell reprogramming provides an outstanding opportunity for the artificial generation of stem cells for regenerative medicine approaches in the clinic. As current cell reprogramming methods are low in efficiency, researchers around the globe aim to learn lessons from the early embryo which might lead them to a more efficient and faster generation of high-quality, fully reprogrammed stem cells.

Prof. Maria-Elena Torres-Padilla, Director of the Institute of Epigenetics and Stem Cells at Helmholtz Zentrum München and her colleague Dr. Adam Burton are doing pioneering work in this field.

Why would we want to reprogram cells?

Maria-Elena: Can you imagine being able to artificially generate cells that can develop into any cell type? That would be really fantastic! We call this ability ‘totipotency’ and it is the highest level of cellular plasticity. When you think about using healthy cells to replace sick cells, for example in regeneration and replacement therapies, you need to think about how to generate those ‘new’ healthy cells. For that, you often need to ‘reprogram’ other cells, that means, to be able to change one cell into the cell type of interest.

In nature, cellular reprogramming happens in the early embryo at fertilization. It is a purely epigenetic process since the DNA content of the embryo’s cells does not change, only the genes they express. Epigenetics mediates changes in gene expression meaning the way our genes are ‘read’ from our genetic makeup, which is largely imposed by chromatin. Chromatin is the structure, in which the DNA of a cell is packed into, so that it can fit into the tiny nucleus of a cell, and heterochromatin refers to the part of our DNA that is tightly packed and not accessible.

Heterochromatin is known to be a major bottleneck for artificial cell reprogramming. In embryos, however, the process of cell reprogramming is extremely efficient, some people even think that it is 100% efficient. Therefore, we wanted to understand how the embryo ‘keeps heterochromatin in check’ so that reprogramming can occur. Adopting strategies for reprogramming based on our knowledge of how the embryo does it, is very promising. These strategies can help us to increase the efficiency of reprogramming for regenerative medicine — an outstanding opportunity and research priority of the years to come.

How does the embryo deal with heterochromatin?

Adam: Heterochromatin is tightly controlled in the embryo from early on. In a mouse model, we saw that the histone* modification H3K9me3, which is the classical marker of heterochromatin, is in fact present in the embryo from early on. Usually, H3K9me3 correlates strongly with gene silencing, meaning that the genes cannot be ‘read’ from our genetic makeup. However, we observed that in the very early embryo, this is surprisingly not the case and that H3K9me3 is compatible with gene expression! One of our major findings was to discover that the enzyme, which adds the H3K9me3 mark to the histone, is inhibited by a non-coding RNA, that means there is an active process in the early embryo that counteracts the establishment of fully functional heterochromatin. Globally, we concluded that heterochromatin in the early mammalian embryo is immature because it cannot fulfill its typical function. This is probably due to the absence of other critical heterochromatic factors, which we are now also currently investigating.

How could we use this new knowledge for artificial cell reprogramming?

Maria-Elena: Essentially, what our work documents is a potential way to ‘tune’ down heterochromatin. These findings will provide us with the factors that we can manipulate for making artificial cell reprogramming more efficient and achieve higher cell conversion rates. The key take-home message is that we can learn from the epigenetic remodeling that occurs during the natural process of reprogramming in embryos at fertilization and can transfer this knowledge to improve currently inefficient artificial reprogramming strategies. In fact, learning lessons from the embryo will enable the more efficient and timely generation of high-quality, fully reprogrammed stem cells, which are vital for the full implementation of regenerative medicine approaches in the clinic.

*Histones are basic proteins that are important for the packaging of the DNA into chromatin. The DNA wraps around a histone octamer and this structure is known as nucleosome. Generally, chromatin consists of arrays of nucleosomes and under the microscope this structure looks like beads-on-a-string.

Source link

News

Collective cell dynamics could define stem cells identity, number, and dynamics — ScienceDaily

Without stem cells, human life would not exist. Due to them, a lump of cells becomes an organ, and a fertilized egg develops into a baby. But what actually makes a stem cell? Are these a stable population of specially gifted cells? Scientists discovered that instead, stem cells might emerge due to the collective behavior of cells within the organs.

Stem cells are central to organ development and renewal. In most organs, stem cells are located in specific regions and, in some cases, can be identified through several intrinsic properties, like molecular markers. They can differentiate into various types of cells and divide indefinitely to produce more stem cells. However, does this mean the stem cell at the top is immortal? Or can any cell overthrow this? The scientific community is in an open debate whether stem cells actually arise from intrinsic cell properties or from the collective dynamics of the tissue itself. In this second scenario, potential stem cells are in constant competition to sit in certain “niche” regions. Each cell wants to overtake its neighbor by replication and, therefore, continuously pushes them. The functional stem cell will be the one that wins this competition, while losers will be pushed away from the niche, differentiate, and ultimately die.

Here, the Hannezo group at IST Austria looked at the mechanism to overcome such pushing forces away from the niche, in collaboration with researchers from the National Cancer Institute of Netherlands and the University of Cambridge. They used a live-imaging microscope to record stem cell movements in the breast, intestine, and kidney tissue. The team found that in addition to constant flow and pushing forces, many random movements were observed. Why would those be important? “A famous saying in real estate business is “location, location, location.” In the case of stem cells, this saying transfers to a location determining stemness (rather than the other way around). Then, random movements become key, as they allow you to get to the right location even if you started in the wrong one.” summarizes Edouard Hannezo.

Under that framework, the tissues look like the exit of the subway station in the rush hour, with some people able to randomly turn back against the drift of the mass, trying to take the subway again. Under this metaphor, random movements are key to allow cells away from the stem cell niche to eventually go back to it. “We wanted to know what defines the number and dynamics of the stem cells, and to what extent this could be answered by mathematically exploring only the movements of the cells and the geometry of the organs,” says Bernat Corominas-Murtra, the leading scientist in this study. They then mathematically mapped this noisy cell dynamics into the geometry of the organs and could predict, among others, the number of functional stem cells (the ones that can get to the right location in time, given the amount of noise/mobility in the system). They found that during tissue renewal or growth, stem cell regions developed naturally, without needing to make assumptions on the molecular nature of the cells. Therefore, the scientists showed that the dynamics and geometry alone play an essential role.

Bernat Corominas-Murtra describes their results: “You would expect that the randomness of cell movements blurs the properties of the system or makes it more unstable. Instead, it is key for the emergence of robust, complex patterns like the stem cell region, which remarkably coincides with the one previously identified using biomolecular markers of individual cells.” These results contribute to the open debate on the nature of stem cells in tissues and potentially opens a new dimension in the understanding of organ renewal.

Story Source:

Materials provided by Institute of Science and Technology Austria. Note: Content may be edited for style and length.

Source link

News

Research uses stem cell technology to learn how coronavirus may directly attack heart muscle — ScienceDaily

A new study shows that SARS-CoV-2, the virus that causes COVID-19 (coronavirus), can infect heart cells in a lab dish, indicating it may be possible for heart cells in COVID-19 patients to be directly infected by the virus. The discovery, published today in the journal Cell Reports Medicine, was made using heart muscle cells that were produced by stem cell technology.

Although many COVID-19 patients experience heart problems, the reasons are not entirely clear. Pre-existing cardiac conditions or inflammation and oxygen deprivation that result from the infection have all been implicated. But until now, there has been only limited evidence that the SARS-CoV-2 virus directly infects the individual muscle cells of the heart.

“We not only uncovered that these stem cell-derived heart cells are susceptible to infection by novel coronavirus, but that the virus can also quickly divide within the heart muscle cells,” said Arun Sharma, PhD, a research fellow at the Cedars-Sinai Board of Governors Regenerative Medicine Institute and first and co-corresponding author of the study. “Even more significant, the infected heart cells showed changes in their ability to beat after 72 hours of infection.”

The study also demonstrated that human stem cell-derived heart cells infected by SARS-CoV-2 change their gene expression profile, further confirming that the cells can be actively infected by the virus and activate innate cellular “defense mechanisms” in an effort to help clear out the virus.

While these findings are not a perfect replicate of what is happening in the human body, this knowledge may help investigators use stem cell-derived heart cells as a screening platform to identify new antiviral compounds that could alleviate viral infection of the heart, according to senior and co-corresponding author Clive Svendsen, PhD.

“This viral pandemic is predominately defined by respiratory symptoms, but there are also cardiac complications, including arrhythmias, heart failure and viral myocarditis,” said Svendsen, director of the Regenerative Medicine Institute and professor of Biomedical Sciences and Medicine. “While this could be the result of massive inflammation in response to the virus, our data suggest that the heart could also be directly affected by the virus in COVID-19.”

Researchers also found that treatment with an ACE2 antibody was able to blunt viral replication on stem cell-derived heart cells, suggesting that the ACE2 receptor could be used by SARS-CoV-2 to enter human heart muscle cells.

“By blocking the ACE2 protein with an antibody, the virus is not as easily able to bind to the ACE2 protein, and thus cannot easily enter the cell,” said Sharma. “This not only helps us understand the mechanisms of how this virus functions, but also suggests therapeutic approaches that could be used as a potential treatment for SARS-CoV-2 infection.”

The study used human induced pluripotent stem cells (iPSCs), a type of stem cell that is created in the lab from a person’s blood or skin cells. IPSCs can make any cell type found in the body, each one carrying the DNA of the individual. Tissue-specific cells created in this way are used for research and for creating and testing potential disease treatments.

“This work illustrates the power of being able to study human tissue in a dish,” said Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute, who collaborated with Sharma and Svendsen on the study. “It is plausible that direct infection of cardiac muscle cells may contribute to COVID-related heart disease.”

The investigators also collaborated with co-corresponding author Vaithilingaraja Arumugaswami, DVM, PhD, an associate professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. Arumugaswami provided the novel coronavirus that was added to the heart cells, and UCLA researcher Gustavo Garcia Jr. contributed essential heart cell infection experiments.

“This key experimental system could be useful to understand the differences in disease processes of related coronaviral pathogens, SARS and MERS,” Arumugaswami said.

Source link

News

A simpler way to make sensory hearing cells — ScienceDaily

Scientists from the USC Stem Cell laboratories of Neil Segil and Justin Ichida are whispering the secrets of a simpler way to generate the sensory cells of the inner ear. Their approach uses direct reprogramming to produce sensory cells known as “hair cells,” due to their hair-like protrusions that sense sound waves. The study was published in the journal eLife.

“We’ve succeeded in directly reprogramming a variety of mouse cell types into what we’re calling ‘induced hair cell-like cells, or iHCs,” said PhD student Louise Menendez, the study’s lead author. “This allows us to efficiently generate large numbers of iHCs to identify causes and treatments for hearing loss.”

The scientists successfully reprogrammed three different types of mouse cells to become iHCs. The first two types were embryonic and adult versions of connective tissue cells, known as fibroblasts. The third was a different type of inner ear cell, known as a supporting cell.

To achieve reprogramming, the scientists exposed fibroblasts and supporting cells to a cocktail of four transcription factors, which are molecules that help convey the instructions encoded in DNA. The scientists identified this cocktail by testing various combinations of 16 transcription factors that were highly active in the hair cells of newborn mice.

“The four key ingredients turned out to be the transcription factors Six1, Atoh1, Pou4f3, and Gfi1,” said Menendez.

The resulting iHCs resembled naturally occurring hair cells in terms of their structure, electrophysiology, and genetic activity. The iHCs also possessed several other distinct characteristics of hair cells, including vulnerability to an antibiotic known to cause hearing loss.

“Hair cells are easy to damage, and currently impossible to repair in humans,” said Segil, a professor in the Department of Stem Cell Biology and Regenerative Medicine, and the USC Tina and Rick Caruso Department of Otolaryngology — Head and Neck Surgery, and one of the corresponding authors of the study. “Aging, loud noises, and certain chemotherapy drugs and antibiotics can all lead to the permanent loss of hair cells, which is the leading contributor to hearing loss worldwide.”

iHCs have the potential to accelerate hearing loss research in at least two important ways, according to Ichida, who is the John Douglas French Alzheimer’s Foundation Associate Professor of Stem Cell Biology and Regenerative Medicine at USC, and the other corresponding author of the study.

“In the near term, researchers can use iHCs to screen large numbers of drug candidates that might prevent or treat hearing loss,” said Ichida, who is also a New York Stem Cell Foundation-Robertson Investigator. “And further in the future, it could become possible to directly reprogram supporting cells in the inner ear of a deafened individual, as a way to restore hearing.”

Story Source:

Materials provided by Keck School of Medicine of USC. Original written by Cristy Lytal. Note: Content may be edited for style and length.

Source link

News

Nanoparticle for overcoming leukemia treatment resistance — ScienceDaily

UConn associate professor of pharmaceutics Xiuling Lu, along with professor of chemistry Rajeswari M. Kasi, was part of a team that recently published a paper in Nature Cell Biology finding a commonly used chemotherapy drug may be repurposed as a treatment for resurgent or chemotherapy-resistant leukemia.

One of the largest problems with cancer treatment is the development of resistance to anticancer therapies. Few FDA-approved products directly target leukemia stem cells, which cause treatment-resistant relapses. The only known method to combat their presence is stem cell transplantation.

Leukemia presents unique treatment challenges due to the nature of this form of cancer. The disease affects bone marrow, which produces blood cells. Leukemia is a cancer of the early blood-forming cells, or stem cells. Most often, leukemia is a cancer of the white blood cells. The first step of treatment is to use chemotherapy to kill the cancerous white blood cells, but if the leukemia stem cells in the bone marrow persist, the cancer may relapse in a therapy-resistant form.

Fifteen to 20% of child and up to two thirds of adult leukemia patients experience relapse. Adults who relapse face a less-than 30% five-year survival rate. For children the five-year survival rate after relapse is around two thirds. When relapse occurs, chemotherapy does not improve the prognosis for these patients. There is a critical need for scientists to develop a therapy that can more effectively target chemotherapy-resistant cells.

There are two cellular pathways, Wnt- β-catenin and PI3K-Akt, which play a key role in stem cell regulation and tumor regenesis. Cooperative activation of the Wnt- β-catenin and PI3K-Akt pathways drives self-renewal of cells that results in leukemic transformation, giving rise to cancer relapse. Previous studies have worked on targeting elements of these pathways individually, which has had limited success and often results in the growth of chemo-resistant clones.

The researchers screened hundreds of drugs to find one that may inhibit this interaction. They identified a commonly used chemotherapy drug, doxorubicin as the most viable target. While this drug is highly toxic and usually used with caution in clinical settings, the team found when used in multiple, low doses, it disrupts the Wnt- β-catenin and PI3K-Akt pathways’ interaction, while potentially reducing toxicity.

Lu’s lab contributed a nanoparticle which allowed the drug to be injected safely and released sustainably over time, a key to the experiment’s success. The nanoparticle encasing doxorubicin enables slow release of the drug to the bone marrow to reduce the Akt-activated Wnt– β-catenin levels in chemo-resistant leukemic stem cells and reduce the tumorigenic activity. In low doses, doxorubicin stimulated the immune system while typical clinical doses are immunosuppressive, inhibiting healthy immune cells.

Lu is the CEO of Nami Therapeutics, a startup which designs nanoparticles for drug delivery in a variety of clinical contexts including cancer treatment and vaccine delivery.

Because of its rate of drug release, Lu’s patented nanoparticle was more effective than both a solution of the pure drug and a liposomal doxorubicin, the only commercially available version of a nanoparticle carrying doxorubicin.

“It’s exciting that the whole research team identified this new mechanism to effectively inhibit leukemia stem cells,” Lu says. “We are happy to see that our proprietary nanoparticle delivery system has such potential to help patients.”

By using low, but more sustained, doses of this drug, leukemia-initiating activity of cancerous stem cells was effectively inhibited.

The researchers demonstrated clinical relevance by transplanting patient leukemic cells into mice and observing that low-dose doxorubicin’s ability to disrupt these cells. Patient sample transplants with therapy-resistant leukemia stem cells rapidly developed leukemia. But the low-dose doxorubicin nanoparticle treatment improved survival by reducing the presence of leukemia stem cells.

Lu says the next steps for this research is to further validate the now-patented method and nanoparticle and eventually bring it into clinical usage. Lu and her collaborator, Rajeswari Kasi, also have two pending patents on copolymer-nanoparticles for drug delivery and methods for treating chemo-resistant cancer-initiating cells.

Source link

News

Cord blood for stem cell transplant may outperform matched sibling donor — ScienceDaily

When a cancer patient needs a bone marrow transplant, there are four common donor sources: A matched related donor (sibling), a matched unrelated donor (from a donor database), a half-matched donor, or umbilical cord blood. Of course, there are plusses and minuses to each approach, but consensus has generally ranked a matched sibling first, followed by a matched unrelated donor, with cord blood and half-matched donors reserved for patients without either of the first two options.

Now a University of Colorado Cancer Center study based on a decade of research and treatment may reshuffle this list. In fact, the comparison of 190 patients receiving cord-blood transplants with 123 patients receiving transplants from the “gold standard” of matched sibling donors showed no difference in survival outcomes between these two approaches, with significantly fewer complications due to chronic graft-versus-host disease in patients receiving transplants from cord blood.

“Our cord blood patients were doing as well as patients receiving transplants from matched siblings, and in selected populations cord blood patients were doing even better. Our program at CU Cancer Center is somewhat unique in its emphasis on cord blood as a donor source for stem cell transplants and this study is an affirmation of why we do what we do here,” says Jonathan Gutman, MD, CU Cancer Center investigator and director of the allogeneic stem cell transplantation program at UCHealth University of Colorado Hospital.

In addition to showing a decrease in the chance of graft-versus-host disease, which develops when a transplanted blood system attacks a patient’s tissues, the study shows a slightly lower rate of relapse in these patients undergoing transplant with cord blood.

“Especially with younger, fitter patients who we can hit harder in the transplant process, we have strong hints here that cord blood may be actively better in terms of reducing both graft-versus-host disease and relapse,” Gutman says.

Umbilical cord blood, which is banked for public use at designated centers around the world, is rich in stem cells, which can repopulate a patient’s blood system. Because these umbilical cord stem cells are more “basic” than adult blood cells, they require a lower degree of match than blood cells from an adult donor. However, one challenge has been obtaining enough of these cells to perform a successful transplant.

“It turns out that for adults, it’s very hard to find a single cord blood unit that meets the parameters we know need to be met in terms of size. To overcome this barrier, we often use two units from different sources,” Gutmans says. Also, research at CU Cancer Center and elsewhere is developing techniques to expand small samples of banked cord blood to the volume needed for transplant.

“We think there are important advantages of cord blood, especially with respect to graft-versus-host disease,” Gutman says. “Previously, we’ve taken a position recommending cord blood over matched unrelated donors, and now we show that cord blood may even out-compete the gold standard of matched sibling donors.”

Story Source:

Materials provided by University of Colorado Anschutz Medical Campus. Original written by Garth Sundem. Note: Content may be edited for style and length.

Source link

News

Texas A&M researchers say these grafts could be used to promote swift and precise bone healing — ScienceDaily

Although most broken bones can be mended with a firm cast and a generous measure of tender loving care, more complicated fractures require treatments like bone grafting. Researchers at Texas A&M University have now created superior bone grafts using primitive stem cells. They found that these cells help create very fertile scaffolds needed for bone to regenerate at the site of repair.

The researchers said these grafts could be used to promote swift and precise bone healing so that patients maximally benefit from the surgical intervention.

“There are several problems that can occur with orthopedic implants, like inflammation and pain. Also, they can loosen, requiring revision surgeries that are often more complicated than the original surgery to put in the implant,” Dr. Roland Kaunas, associate professor in the Department of Biomedical Engineering and a corresponding author on the study. “So, by speeding up the bone healing process, our material can potentially reduce the number of these revision surgeries.”

The researchers have published their findings in the June issue of the journal Nature Communications.

Each year, around 600,000 people in the United States experience delayed or incomplete bone healing. For some of these cases, physicians turn to surgical procedures that involve transplanting bone tissue to the repair site. These bone grafts have generally come from two sources: the patient’s own bone from another location on the body called autografts, or highly-processed human cadaver bones.

However, both types of bone grafts have their share of drawbacks. For example, autografts require additional surgery for bone tissue extraction, increasing the recovery time for patients and sometimes, chronic pain. On the other hand, grafts derived from cadaver bone preclude the need for two surgeries, but these transplants tend to be devoid of many of the biomolecules that promote bone repair.

“Grafts from cadaver bone have some of the physical properties of bone, and even a little bit of the biological essence but they are very depleted in terms of their functionality,” said Dr. Carl Gregory, associate professor at the Texas A&M Health Science Center, also a corresponding author on the study. “What we wanted to do was engineer a bone graft where we could experimentally crank up the gears, so to speak, and make it more biologically active.”

Previous studies have shown that stem cells, particularly a type called mesenchymal stem cells, can be used to produce bone grafts that are biologically active. In particular, these cells convert to bone cells that produce the materials required to make a scaffolding, or the extracellular matrix, that bones need for their growth and survival.

However, these stem cells are usually extracted from the marrow of an adult bone and are, as a result, older. Their age affects the cells’ ability to divide and produce more of the precious extracellular matrix, Kaunas said.

To circumvent this problem, the researchers turned to the cellular ancestors of mesenchymal stem cells, called pluripotent stem cells. Unlike adult mesenchymal cells that have a relatively short lifetime, they noted that these primitive cells can keep proliferating, thereby creating an unlimited supply of mesenchymal stem cells needed to make the extracellular matrix for bone grafts. They added that pluripotent cells can be made by genetically reprogramming donated adult cells.

When the researchers experimentally induced the pluripotent stem cells to make brand new mesenchymal stem cells, they were able to generate an extracellular matrix that was far more biologically active compared to that generated by mesenchymal cells obtained from adult bone.

“Our materials were not just enriched in the biological molecules that are required to make the chunky part of bone tissue but also growth factors that drive blood vessel formation,” said Gregory.

To test the efficacy of their scaffolding material as a bone graft, they then carefully extracted and purified the enriched extracellular matrix and then implanted it at a site of bone defects. Upon examining the status of bone repair in a few weeks, they found that their pluripotent stem-cell-derived matrix was five to sixfold more effective than the best FDA-approved graft stimulator.

“Bone repair assays using the gold standard of grafts, like those administered with the powerful bone growth stimulator called bone morphogenic protein-2, can take about eight weeks, but we were getting complete healing in four weeks,” said Gregory. “So, under these conditions, our material surpassed the efficacy of bone morphogenic protein-2 by a longshot, indicating that it is a vast improvement of current bone repair technologies.”

The researchers also said that from a clinical standpoint, the grafts can be incorporated into numerous engineered implants, such as 3D-printed implants or metal screws, so that these parts integrate better with the surrounding bone. They also noted that the bone grafts will also be easier to produce and hence are advantageous from a manufacturing standpoint.

“Our material is very promising because the pluripotent stem cells can ideally generate many batches of the extracellular matrix from just a single donor which will greatly simplify the large-scale manufacturing of these bone grafts,” said Kaunas.

Source link

1 2 3 8 9
Privacy Settings
We use cookies to enhance your experience while using our website. If you are using our Services via a browser you can restrict, block or remove cookies through your web browser settings. We also use content and scripts from third parties that may use tracking technologies. You can selectively provide your consent below to allow such third party embeds. For complete information about the cookies we use, data we collect and how we process them, please check our Privacy Policy
Youtube
Consent to display content from Youtube
Vimeo
Consent to display content from Vimeo
Google Maps
Consent to display content from Google
Spotify
Consent to display content from Spotify
Sound Cloud
Consent to display content from Sound
Cart Overview