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March 2020

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Cancer study may accidentally help researchers create usable blood stem cells — ScienceDaily

A massive research effort over more than a quarter century has tried to make personalized blood stem cells for use in treating leukemias, among many other uses. One way researchers have gone about this is to sample a patient’s adult cells and then “deprogram” them to create induced pluripotent stem cells (iPSCs), which are capable of forming any of the body’s cell types, including blood cells. Unfortunately, these iPSCs also have the potential to become cancer. So researchers have largely refocused their efforts on making hematopoietic stem cells (HSCs), which can’t make any cell type, but can produce many types of blood cells. The good news is that HSCs don’t seem to cause cancer like iPCs. The bad news is that researchers have been unable to create HSCs that can take hold and grow in the body.

Now a University of Colorado Cancer Center study identifies a possible new way to convince pluripotent cells to make HSCs. And, ironically, a possible way to do this lies in magnifying a gene that causes a form of childhood leukemia.

“My lab was working on a gene called MLL that, when accidentally fused together with another gene, causes childhood leukemia,” says Patricia Ernst, PhD, CU Cancer Center investigator and Professor in the CU School of Medicine Departments of Pediatrics.

In other words, this malfunctioning form of the gene MLL is bad and Ernst (among others) hoped to discover how to mute the function of this cancer-causing fusion gene. But to understand how to counteract malfunctioning MLL, Ernst and her team needed to know how regular MLL works.

“Half my lab was studying MLL’s role in leukemia and the other half was exploring what MLL normally does,” Ernst says. “When we knocked out this gene, we saw that hematopoietic stem cells couldn’t retain their ‘stemness’ — instead of being HSCs, they would differentiate to become like normal cells of the blood system. So we wondered what would happen if we increased it,” Ernst says.

The current paper, highlighted on the cover of the current issue of the journal Stem Cell Reports, is the result of that question.

What Ernst’s studies show is that doubling the amount of the regular MLL protein in pluripotent stem cells, can push these cells to produce more blood cells. The finding may help to develop usable HSCs that could regrow a leukemia patient’s blood system after the chemotherapy and irradiation used to kill the cancer.

Second, the finding has important ramifications for ongoing drug development against MLL-rearranged childhood leukemia, namely that drugs affecting the healthy MLL gene along with the rearranged form of the MLL gene may have negative consequences for blood functions.

“It’s about selective targeting,” Ernst says. “We want to selectively turn off the cancer-causing MLL fusion gene without affecting the regular form of the MLL gene.”

With a pilot grant from the CU Cancer Center RNA Biosciences Initiative, Ernst and her team were able to drill down to see the function of MLL at a single-cell level.

“As pluripotent cells differentiate, they enter a kind of transitional state in which they still have the potential to become many different cell types. Single-cell sequencing let us watch the fate of these transitional cells, and we saw that activating MLL led to more of these transitional cells becoming blood cell types,” Ernst says.

One way to activate MLL in a population of pluripotent cells would be with genetic engineering, adding additional copies of the MLL gene to the pluripotent cells’ genome. However, that approach is not practical in human patients. Instead, Ernst plans to pursue development of a drug-based method to amplify the level of existing MLL.

The goal is to “make customizable stem cell products that could be adapted to any particular patient,” Ernst says.

The finding of MLL’s role in stem cell differentiation and maintenance provides an important new starting point in a field of study that has seen many dead ends.

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

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‘Primitive’ stem cells shown to regenerate blood vessels in the eye — ScienceDaily

Johns Hopkins Medicine scientists say they have successfully turned back the biological hands of time, coaxing adult human cells in the laboratory to revert to a primitive state, and unlocking their potential to replace and repair damage to blood vessels in the retina caused by diabetes. The findings from this experimental study, they say, advance regenerative medicine techniques aimed at reversing the course of diabetic retinopathy and other blinding eye diseases.

“Our study results bring us a step closer to using stem cells more widely in regenerative medicine, without the historical problems our field has encountered in getting such cells to differentiate and avoid becoming cancerous,” says Elias Zambidis, M.D., Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center and a member of Johns Hopkins’ Institute for Cell Engineering.

Results of experiments using human cells and mice were published online March 5 in Nature Communications.

According to the National Eye Institute, diabetic retinopathy is a leading cause of blindness in U.S. adults. By 2050, researchers estimate that some 14.6 million Americans will have the condition, which results in abnormal blood vessel growth in the retina, where light is processed into vision.

For the study, the scientists began their experiments with a fibroblast — a connective tissue cell — taken from a person with type 1 diabetes. Reprogrammed fibroblasts function as “stem” cells, with the potential to give rise to all tissues in the body, including blood vessels.

The Johns Hopkins team, including research associate Tea Soon Park, Ph.D., reprogrammed the fibroblast stem cells to revert to a state that is even more primitive than that of conventional human induced pluripotent stem cells — more like the state of embryonic cells about six days after fertilization. This is when cells are the most “naive,” or more capable of developing into any specialized type of cell with a much higher efficiency than conventional human induced pluripotent stem cells.

To do this, the scientists bathe the cells in a cocktail of nutrients and chemicals. What should go into the cocktail to build a better naive stem cell has been a subject of debate over the past decade.

Zambidis’ team used a cocktail mixture of two drugs that other scientists previously used to reprogram stem cells: GSK3β inhibitor CHIR99021, which blocks carbohydrate storage in cells, and MEK inhibitor PD0325901, an experimental anti-cancer drug that can block cancer cell growth. The team had also looked at the potential of a third drug, a PARP inhibitor — a popular anticancer drug used to treat a variety of cancers including those of the ovaries and breast.

To the researchers’ surprise, Zambidis says, the trifecta of MEK, GSK3β and PARP inhibitors worked to wind back the cells’ biological clock. He calls the cocktail 3i, named for the three inhibitors. Zambidis’ team had first reported experiments using the three-drug cocktail in 2016.

For the new study, the research team tracked the reprogrammed stem cells’ molecular profile, including measures of proteins such as NANOG, NR5A2, DPPA3 and E-cadherin that guide cell differentiation. That profile appeared similar to that found in so-called naive epiblast cells, the primitive cells that make up an approximately six day-old human embryo.

The scientists also found that the stem cells reprogrammed with the 3i cocktail did not have abnormal changes in factors that can alter core DNA, called epigenetics, that typically plague other lab-made versions of naive stem cells.

Finally, the research team injected cells called vascular progenitors, which were made from the naive stem cells and are capable of making new blood vessels, into the eyes of mice bred to have a form of diabetic retinopathy that results from blood vessels closing off in the retina. They found that the naive vascular progenitors migrated into the retina’s innermost tissue layer that encircles the eye, with higher efficiencies than have been reported with vascular cells made from conventional stem cell approaches. The naive vascular cells took root there, and most survived in the retina for the duration of the four-week study.

“Interestingly, the 3i ‘naive reprogramming’ cocktail appeared to erase disease-associated epigenetics in the donor cells, and brought them back to a healthy, pristine non-diabetic stem cell state,” says Zambidis.

For comparison, the team reprogrammed diabetic fibroblasts to non-naive stem cells using standard methods, and the resulting vascular progenitor cells failed to migrate as deeply into the retina or survive the length of the study.

Zambidis, Park and the other research team members say more experiments are needed to refine the 3i cocktail and to study the regenerative capacity of the stem cells they grow from the cocktail.

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Scientists uncover link between the nervous system and stem cells that regenerate pigment — ScienceDaily

When Marie Antoinette was captured during the French Revolution, her hair reportedly turned white overnight. In more recent history, John McCain experienced severe injuries as a prisoner of war during the Vietnam War — and lost color in his hair.

For a long time, anecdotes have connected stressful experiences with the phenomenon of hair graying. Now, for the first time, Harvard University scientists have discovered exactly how the process plays out: stress activates nerves that are part of the fight-or-flight response, which in turn cause permanent damage to pigment-regenerating stem cells in hair follicles.

The study, published in Nature, advances scientists’ knowledge of how stress can impact the body.

“Everyone has an anecdote to share about how stress affects their body, particularly in their skin and hair — the only tissues we can see from the outside,” said senior author Ya-Chieh Hsu, the Alvin and Esta Star Associate Professor of Stem Cell and Regenerative Biology at Harvard. “We wanted to understand if this connection is true, and if so, how stress leads to changes in diverse tissues. Hair pigmentation is such an accessible and tractable system to start with — and besides, we were genuinely curious to see if stress indeed leads to hair graying. “

Narrowing down the culprit

Because stress affects the whole body, researchers first had to narrow down which body system was responsible for connecting stress to hair color. The team first hypothesized that stress causes an immune attack on pigment-producing cells. However, when mice lacking immune cells still showed hair graying, researchers turned to the hormone cortisol. But once more, it was a dead end.

“Stress always elevates levels of the hormone cortisol in the body, so we thought that cortisol might play a role,” Hsu said. “But surprisingly, when we removed the adrenal gland from the mice so that they couldn’t produce cortisol-like hormones, their hair still turned gray under stress.”

After systematically eliminating different possibilities, researchers honed in on the sympathetic nerve system, which is responsible for the body’s fight-or-flight response.

Sympathetic nerves branch out into each hair follicle on the skin. The researchers found that stress causes these nerves to release the chemical norepinephrine, which gets taken up by nearby pigment-regenerating stem cells.

Permanent damage

In the hair follicle, certain stem cells act as a reservoir of pigment-producing cells. When hair regenerates, some of the stem cells convert into pigment-producing cells that color the hair.

Researchers found that the norepinephrine from sympathetic nerves causes the stem cells to activate excessively. The stem cells all convert into pigment-producing cells, prematurely depleting the reservoir.

“When we started to study this, I expected that stress was bad for the body — but the detrimental impact of stress that we discovered was beyond what I imagined,” Hsu said. “After just a few days, all of the pigment-regenerating stem cells were lost. Once they’re gone, you can’t regenerate pigment anymore. The damage is permanent.”

The finding underscores the negative side effects of an otherwise protective evolutionary response, the researchers said.

“Acute stress, particularly the fight-or-flight response, has been traditionally viewed to be beneficial for an animal’s survival. But in this case, acute stress causes permanent depletion of stem cells,” said postdoctoral fellow Bing Zhang, the lead author of the study.

Answering a fundamental question

To connect stress with hair graying, the researchers started with a whole-body response and progressively zoomed into individual organ systems, cell-to-cell interaction and, eventually, all the way down to molecular dynamics. The process required a variety of research tools along the way, including methods to manipulate organs, nerves, and cell receptors.

“To go from the highest level to the smallest detail, we collaborated with many scientists across a wide range of disciplines, using a combination of different approaches to solve a very fundamental biological question,” Zhang said.

The collaborators included Isaac Chiu, assistant professor of immunology at Harvard Medical School who studies the interplay between nervous and immune systems.

“We know that peripheral neurons powerfully regulate organ function, blood vessels, and immunity, but less is known about how they regulate stem cells,” Chiu said.

“With this study, we now know that neurons can control stem cells and their function, and can explain how they interact at the cellular and molecular level to link stress with hair graying.”

The findings can help illuminate the broader effects of stress on various organs and tissues. This understanding will pave the way for new studies that seek to modify or block the damaging effects of stress.

“By understanding precisely how stress affects stem cells that regenerate pigment, we’ve laid the groundwork for understanding how stress affects other tissues and organs in the body,” Hsu said. “Understanding how our tissues change under stress is the first critical step towards eventual treatment that can halt or revert the detrimental impact of stress. We still have a lot to learn in this area.”

The study was supported by the Smith Family Foundation Odyssey Award, the Pew Charitable Trusts, Harvard Stem Cell Institute, Harvard/MIT Basic Neuroscience Grants Program, Harvard FAS and HMS Dean’s Award, American Cancer Society, NIH, the Charles A. King Trust Postdoctoral Fellowship Program, and an HSCI junior faculty grant.

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Therapy shown to relieve extreme pain in mice; now moving towards human trials — ScienceDaily

Researchers at the University of Sydney have used human stem cells to make pain-killing neurons that provide lasting relief in mice, without side effects, in a single treatment.

The next step is to perform extensive safety tests in rodents and pigs, and then move to human patients suffering chronic pain within the next five years.

If the tests are successful in humans, it could be a major breakthrough in the development of new non-opioid, non-addictive pain management strategies for patients, the researchers said.

“We are already moving towards testing in humans,” said Associate Professor Greg Neely, a leader in pain research at the Charles Perkins Centre and the School of Life and Environmental Sciences.

“Nerve injury can lead to devastating neuropathic pain and for the majority of patients there are no effective therapies. This breakthrough means for some of these patients, we could make pain-killing transplants from their own cells, and the cells can then reverse the underlying cause of pain.”

Published today in the peer-reviewed journal Pain, the team used human induced pluripotent stem cells (iPSC) derived from bone marrow to make pain-killing cells in the lab, then put them into the spinal cord of mice with serious neuropathic pain. The development of iPSC won a Nobel Prize in 2012.

“Remarkably, the stem-cell neurons promoted lasting pain relief without side effects,” co-senior author Dr Leslie Caron said. “It means transplant therapy could be an effective and long-lasting treatment for neuropathic pain. It is very exciting.”

John Manion, a PhD student and lead author of the paper said: “Because we can pick where we put our pain-killing neurons, we can target only the parts of the body that are in pain. This means our approach can have fewer side effects.”

The stem cells used were derived from adult blood samples.

The total cost of chronic pain in Australia in 2018 was estimated to be $139.3 billion.

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

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Researchers discover new stem cells that can generate new bone — ScienceDaily

A population of stem cells with the ability to generate new bone has been newly discovered by a group of researchers at the UConn School of Dental Medicine.

In the journal STEM CELLS, lead investigator Dr. Ivo Kalajzic, professor of reconstructive sciences, postdoctoral fellows Dr. Sierra Root and Dr. Natalie Wee, and collaborators at Harvard, Maine Medical Research Center, and the University of Auckland present a new population of cells that reside along the vascular channels that stretch across the bone and connect the inner and outer parts of the bone.

“This is a new discovery of perivascular cells residing within the bone itself that can generate new bone forming cells,” said Kalajzic. “These cells likely regulate bone formation or participate in bone mass maintenance and repair.”

Stem cells for bone have long been thought to be present within bone marrow and the outer surface of bone, serving as reserve cells that constantly generate new bone or participate in bone repair. Recent studies have described the existence of a network of vascular channels that helped distribute blood cells out of the bone marrow, but no research has proved the existence of cells within these channels that have the ability to form new bones.

In this study, Kalajzic and his team are the first to report the existence of these progenitor cells within cortical bone that can generate new bone-forming cells — osteoblasts — that can be used to help remodel a bone.

To reach this conclusion, the researchers observed the stem cells within an ex vivo bone transplantation model. These cells migrated out of the transplant, and began to reconstruct the bone marrow cavity and form new bone.

While this study shows there is a population of cells that can help aid bone formation, more research needs to be done to determine the cells’ potential to regulate bone formation and resorption.

This study was funded by the Regenerative Medicine Research Fund (RMRF; 16-RMB-UCHC-10) by CT Innovations and by National Institute of Arthritis and Musculoskeletal and Skin.

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

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Treatment uses person’s own stem cells instead of donor cells — ScienceDaily

UCLA researchers are part of an international team that reported the use of a stem cell gene therapy to treat nine people with the rare, inherited blood disease known as X-linked chronic granulomatous disease, or X-CGD. Six of those patients are now in remission and have stopped other treatments. Before now, people with X-CGD — which causes recurrent infections, prolonged hospitalizations for treatment, and a shortened lifespan — had to rely on bone marrow donations for a chance at remission.

“With this gene therapy, you can use a patient’s own stem cells instead of donor cells for a transplant,” said Dr. Donald Kohn, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and a senior author of the new paper, published today in the journal Nature Medicine. “This means the cells are perfectly matched to the patient and it should be a much safer transplant, without the risks of rejection.”

People with chronic granulomatous disease, or CGD, have a genetic mutation in one of five genes that help white blood cells attack and destroy bacteria and fungus using a burst of chemicals. Without this defensive chemical burst, patients with the disease are much more susceptible to infections than most people. The infections can be severe to life-threatening, including infections of the skin or bone and abscesses in organs such as lungs, liver or brain. The most common form of CGD is a subtype called X-CGD, which affects only males and is caused by a mutation in a gene found on the X-chromosome.

Other than treating infections as they occur and taking rotating courses of preventive antibiotics, the only treatment option for people with CGD is to receive a bone marrow transplant from a healthy matched donor. Bone marrow contains stem cells called hematopoietic, or blood-forming, stem cells, which produce white blood cells. Bone marrow from a healthy donor can produce functioning white blood cells that effectively ward off infection. But it can be difficult to identify a healthy matched bone marrow donor and the recovery from the transplant can have complications such as graft versus host disease, and risks of infection and transplant rejection.

“Patients can certainly get better with these bone marrow transplants, but it requires finding a matched donor and even with a match, there are risks,” Kohn said. Patients must take anti-rejection drugs for six to 12 months so that their bodies don’t attack the foreign bone marrow.

In the new approach, Kohn teamed up with collaborators at the United Kingdom’s National Health Service, France-based Genethon, the U.S. National Institute of Allergy and Infectious Diseases at the National Institutes of Health, and Boston Children’s Hospital. The researchers removed hematopoietic stem cells from X-CGD patients and modified the cells in the laboratory to correct the genetic mutation. Then, the patients’ own genetically modified stem cells — now healthy and able to produce white blood cells that can make the immune-boosting burst of chemicals — were transplanted back into their own bodies. While the approach is new in X-CGD, Kohn previously pioneered a similar stem cell gene therapy to effectively cure a form of severe combined immune deficiency (also known as bubble baby disease) in more than 50 babies.

The viral delivery system for the X-CGD gene therapy was developed and fine-tuned by Professor Adrian Thrasher’s team at Great Ormond Street Hospital, or GOSH, in London, who collaborated with Kohn. The patients ranged in age from 2 to 27 years old; four were treated at GOSH and five were treated in the U.S., including one patient at UCLA Health.

Two people in the new study died within three months of receiving the treatment due to severe infections that they had already been battling before gene therapy. The seven surviving patients were followed for 12 to 36 months after receiving the stem cell gene therapy. All remained free of new CGD-related infections, and six of the seven have been able to discontinue their usual preventive antibiotics.

“None of the patients had complications that you might normally see from donor cells and the results were as good as you’d get from a donor transplant — or better,” Kohn said.

An additional four patients have been treated since the new paper was written; all are currently free of new CGD-related infections and no complications have arisen.

Orchard Therapeutics, a biotechnology company of which Kohn is a scientific co-founder, acquired the rights to the X-CGD investigational gene therapy from Genethon. Orchard will work with regulators in the U.S. and Europe to carry out a larger clinical trial to further study this innovative treatment. The aim is to apply for regulatory approval to make the treatment commercially available, Kohn said.

Kohn and his colleagues plan to develop similar treatments for the other forms of CGD — caused by four other genetic mutations that affect the same immune function as X-CGD.

“Beyond CGD, there are also other diseases caused by proteins missing in white blood cells that could be treated in similar ways,” Kohn said.

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After a bone injury, shape-shifting cells rush to the rescue — ScienceDaily

Conventional thinking is that bone regeneration is left to a small number of mighty cells called skeletal stem cells, which reside within larger groups of bone marrow stromal cells.

But new findings from the University of Michigan recasts that thinking.

In a recent study, Noriaki Ono, assistant professor at the U-M School of Dentistry, and colleagues report that mature bone marrow stromal cells metamorphosed to perform in ways similar to their bone-healing stem cell cousins — but only after an injury.

Bone fracture is an emergency for humans and all vertebrates, so the sooner cells start the business of healing damaged bone — and the more cells there are to do it — the better.

“Our study shows that other cells besides skeletal stem cells can do this job as well,” Ono said.

In the mouse study, inert Cxcl12 cells in bone marrow responded to post-injury cellular cues by converting into regenerative cells, much like skeletal stem cells. Normally, the main job of these Cxcl12-expressing cells, widely known as CAR cells, is to secrete cytokines, which help regulate neighboring blood cells. They were recruited for healing only after an injury.

“The surprise in our study is that these cells essentially did nothing in terms of making bones, when bones grow longer,” Ono said. “It’s only when bones are injured that these cells start rushing to repair the defect.”

This is important because the remarkable regenerative potential of bones is generally attributed to rare skeletal stem cells, Ono says. These new findings raise the possibility that these mighty skeletal stem cells could be generated through the transformation of the more available mature stromal cells.

These mature stromal cells are malleable and readily available throughout life, and could potentially provide an excellent cellular source for bone and tissue regeneration, Ono says.

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

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New injection technique may boost spinal cord injury repair efforts — ScienceDaily

Writing in the journal Stem Cells Translational Medicine, an international research team, led by physician-scientists at University of California San Diego School of Medicine, describe a new method for delivering neural precursor cells (NSCs) to spinal cord injuries in rats, reducing the risk of further injury and boosting the propagation of potentially reparative cells.

The findings are published in the Jan. 29, 2020 print issue.

NSCs hold great potential for treating a variety of neurodegenerative diseases and injuries to the spinal cord. The stem cells possess the ability to differentiate into multiple types of neural cell, depending upon their environment. As a result, there is great interest and much effort to use these cells to repair spinal cord injuries and effectively restore related functions.

But current spinal cell delivery techniques, said Martin Marsala, MD, professor in the Department of Anesthesiology at UC San Diego School of Medicine, involve direct needle injection into the spinal parenchyma — the primary cord of nerve fibers running through the vertebral column. “As such, there is an inherent risk of (further) spinal tissue injury or intraparechymal bleeding,” said Marsala.

The new technique is less invasive, depositing injected cells into the spinal subpial space — a space between the pial membrane and the superficial layers of the spinal cord.

“This injection technique allows the delivery of high cell numbers from a single injection,” said Marsala. “Cells with proliferative properties, such as glial progenitors, then migrate into the spinal parenchyma and populate over time in multiple spinal segments as well as the brain stem. Injected cells acquire the functional properties consistent with surrounding host cells.”

Marsala, senior author Joseph Ciacci, MD, a neurosurgeon at UC San Diego Health, and colleagues suggest that subpially-injected cells are likely to accelerate and improve treatment potency in cell-replacement therapies for several spinal neurodegenerative disorders in which a broad repopulation by glial cells, such as oligodendrocytes or astrocytes, is desired.

“This may include spinal traumatic injury, amyotrophic lateral sclerosis and multiple sclerosis,” said Ciacci.

The researchers plan to test the cell delivery system in larger preclinical animal models of spinal traumatic injury that more closely mimic human anatomy and size. “The goal is to define the optimal cell dosing and timing of cell delivery after spinal injury, which is associated with the best treatment effect,” said Marsala.

Co-authors include: Kota Kamizato and Takahiro Tadokoro, UC San Diego and University of Ryukyus, Japan; Michael Navarro and Silvia Marsala, UC San Diego; Stefan Juhas, Jana Juhasova, Hana Studenovska and Vladimir Proks, Czech Academy of Sciences; Tom Hazel and Karl Johe, Neuralstem, Inc.; and Shawn Driscoll, Thomas Glenn and Samuel Pfaff, Salk Institute.

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Materials provided by University of California – San Diego. Original written by Scott LaFee. Note: Content may be edited for style and length.

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Egg stem cells do not exist, new study shows — ScienceDaily

Researchers at Karolinska Institutet in Sweden have analysed all cell types in the human ovary and found that the hotly debated so-called egg stem cells do not exist. The results, published in Nature Communications, open the way for research on improved methods of treating involuntary childlessness.

The researchers used single-cell analysis to study more than 24,000 cells collected from ovarian cortex samples of 21 patients. They also analysed cells collected from the ovarian medulla, allowing them to present a complete cell map of the human ovary.

One of the aims of the study was to establish the existence or non-existence of egg stem cells.

“The question is controversial since some research has reported that such cells do exist, while other studies indicate the opposite,” says Fredrik Lanner, researcher in obstetrics and gynaecology at the Department of Clinical Science, Intervention and Technology at Karolinska Institutet, and one of the study’s authors.

The question of whether egg stem cells exist affects issues related to fertility treatment, since stem cells have properties that differ from other cells.

“Involuntary childlessness and female fertility are huge fields of research,” says co-author Pauliina Damdimopoulou, researcher in obstetrics and gynaecology at the same department. “This has been a controversial issue involving the testing of experimental fertility treatments.”

The new study substantiates previously reported findings from animal studies — that egg stem cells do not exist. Instead, these are so-called perivascular cells.

The new comprehensive map of ovarian cells can contribute to the development of improved methods of treating female infertility, says Damdimopoulou.

“The lack of knowledge about what a normal ovary looks like has held back developments,” she says. “This study now lays the ground on which to produce new methods that focus on the egg cells that already exist in the ovary. This could involve letting egg cells mature in test tubes or perhaps developing artificial ovaries in a lab.”

The results of the new study show that the main cell types in the ovary are egg cells, granulosa cells, immune cells, endothelial cells, perivascular cells and stromal cells.

The study was financed with the support of several bodies, including the Swedish Research Council, the Swedish Childhood Cancer Foundation, Horizon2020 (FREIA project), the Ragnar Söderberg Foundation, the Ming Wai Lau Centre for Reparative Medicine, the Centre for Innovative Medicine and Wallenberg Academy Fellows.

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Materials provided by Karolinska Institutet. Note: Content may be edited for style and length.

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Cells carrying Parkinson’s mutation could lead to new model for studying disease — ScienceDaily

Parkinson’s disease researchers have used gene-editing tools to introduce the disorder’s most common genetic mutation into marmoset monkey stem cells and to successfully tamp down cellular chemistry that often goes awry in Parkinson’s patients.

The edited cells are a step toward studying the degenerative neurological disorder in a primate model, which has proven elusive. Parkinson’s, which affects more than 10 million people worldwide, progressively degrades the nervous system, causing characteristic tremors, dangerous loss of muscle control, cardiac and gastrointestinal dysfunction and other issues.

“We know now how to insert a single mutation, a point mutation, into the marmoset stem cell,” says Marina Emborg, professor of medical physics and leader of University of Wisconsin-Madison scientists who published their findings Feb. 26 in the journal Scientific Reports. “This is an exquisite model of Parkinson’s. For testing therapies, this is the perfect platform.”

The researchers used a version of the gene-editing technology CRISPR to change a single nucleotide — one molecule among more than 2.8 billion pairs of them found in a common marmoset’s DNA — in the cells’ genetic code and give them a mutation called G2019S.

In human Parkinson’s patients, the mutation causes abnormal over-activity of an enzyme, a kinase called LRRK2, involved in a cell’s metabolism. Other gene-editing studies have employed methods in which the cells produced both normal and mutated enzymes at the same time. The new study is the first to result in cells that make only enzymes with the G2019S mutation, which makes it easier to study what role this mutation plays in the disease.

“The metabolism inside our stem cells with the mutation was not as efficient as a normal cell, just as we see in Parkinson’s,” says Emborg, whose work is supported by the National Institutes of Health. “Our cells had a shorter life in a dish. And when they were exposed to oxidative stress, they were less resilient to that.”

The mutated cells shared another shortcoming of Parkinson’s: lackluster connections to other cells. Stem cells are an especially powerful research tool because they can develop into many different types of cells found throughout the body. When the researchers spurred their mutated stem cells to differentiate into neurons, they developed fewer branches to connect and communicate with neighboring neurons.

“We can see the impact of these mutations on the cells in the dish, and that gives us a glimpse of what we could see if we used the same genetic principles to introduce the mutation into a marmoset,” says Jenna Kropp Schmidt, a Wisconsin National Primate Research Center scientist and co-author of the study. “A precisely genetically-modified monkey would allow us to monitor disease progression and test new therapeutics to affect the course of the disease.”

The concept has applications in research beyond Parkinson’s.

“We can use some of the same genetic techniques and apply it to create other primate models of human diseases,” Schmidt says.

The researchers also used marmoset stem cells to test a genetic treatment for Parkinson’s. They shortened part of a gene to block LRRK2 production, which made positive changes in cellular metabolism.

“We found no differences in viability between the cells with the truncated kinase and normal cells, which is a big thing. And when we made neurons from these cells, we actually found an increased number of branches,” Emborg says. “This kinase gene target is a good candidate to explore as a potential Parkinson’s therapy.”

This research was supported by grants from the National Institutes of Health (R24OD019803, P51OD011106 and UL1TR000427).

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Materials provided by University of Wisconsin-Madison. Original written by Chris Barncard. Note: Content may be edited for style and length.

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