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How stem cells repair damage from heart attacks — ScienceDaily

Mayo Clinic researchers have uncovered stem cell-activated mechanisms of healing after a heart attack. Stem cells restored cardiac muscle back to its condition before the heart attack, in turn providing a blueprint of how stem cells may work.

The study, published in NPJ Regenerative Medicine, finds that human cardiopoietic cells zero in on damaged proteins to reverse complex changes caused by a heart attack. Cardiopoietic cells are derived from adult stem cell sources of bone marrow.

“The extent of change caused by a heart attack is too great for the heart to repair itself or to prevent further damage from occurring. Notably, however, cardiopoietic stem cell therapy reversed, either fully or partially, two-thirds of these disease-induced changes, such that 85% of all cellular functional categories affected by disease responded favorably to treatment,” says Andre Terzic, M.D., Ph.D., director of Mayo Clinic’s Center for Regenerative Medicine. Dr. Terzic is the senior author of the study.

This new understanding of how stem cells restore heart health could provide the framework for broader applications of stem cell therapy across various conditions.

“The actual mode of action of stem cells in repairing a diseased organ has until now been poorly understood, limiting adoption in clinical care. This study sheds light on the most intimate, yet comprehensive, regenerative mechanisms ? paving a road map for responsible and increasingly informed stem cell application,” says Dr. Terzic.

Heart disease is a leading cause of death in the U.S. Every 40 seconds, someone in the U.S. has a heart attack, according to the Centers for Disease Control and Prevention. During a heart attack, cardiac tissue dies, weakening the heart.

“The response of the diseased heart to cardiopoietic stem cell treatment revealed development and growth of new blood vessels, along with new heart tissue,” adds Kent Arrell, Ph.D., a Mayo Clinic cardiovascular researcher and first author of the study.

The research

Researchers compared the diseased hearts of mice that did not receive human cardiopoietic stem cell therapy with those that did. Using a data science approach to map all the proteins in the heart muscle, researchers identified 4,000 cardiac proteins, more than 10% of which suffered damage by a heart attack.

“While we anticipated that the stem cell treatment would produce a beneficial outcome, we were surprised how far it shifted the state of diseased hearts away from disease and back toward a healthy, pre-disease state,” says Dr. Arrell.

Cardiopoietic stem cells are being tested in advanced clinical trials in heart patients.

“The current findings will enrich the base of knowledge pertinent to stem cell therapies and may have the potential to guide therapeutic regimens in the future,” says Dr. Terzic.

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Materials provided by Mayo Clinic. Original written by Susan Buckles. Note: Content may be edited for style and length.

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Long-term follow-up of the London patient suggests no detectable active HIV virus remains in the patient — ScienceDaily

A study of the second HIV patient to undergo successful stem cell transplantation from donors with a HIV-resistant gene, finds that there was no active viral infection in the patient’s blood 30 months after they stopped anti-retroviral therapy, according to a case report published in The Lancet HIV journal and presented at CROI (Conference on Retroviruses and Opportunistic Infections).

Although there was no active viral infection in the patient’s body, remnants of integrated HIV-1 DNA remained in tissue samples, which were also found in the first patient to be cured of HIV. The authors suggest that these can be regarded as so-called ‘fossils’, as they are unlikely to be capable of reproducing the virus.

Lead author on the study, Professor Ravindra Kumar Gupta, University of Cambridge, UK, says: “We propose that these results represent the second ever case of a patient to be cured of HIV. Our findings show that the success of stem cell transplantation as a cure for HIV, first reported nine years ago in the Berlin patient, can be replicated.”

He cautions: “It is important to note that this curative treatment is high-risk, and only used as a last resort for patients with HIV who also have life-threatening haematological malignancies. Therefore, this is not a treatment that would be offered widely to patients with HIV who are on successful antiretroviral treatment. 

While most HIV patients can manage the virus with current treatment options and have the possibility of living a long and healthy life, experimental research of this kind following patients who have undergone high-risk, last-resort curative treatments, can provide insight into how a more widely applicable cure might be developed in the future.

In 2011, another patient based in Berlin (the ‘Berlin patient’) was the first HIV patient to be reported cured of the virus three and half years after undergoing similar treatment. Their treatment included total body irradiation, two rounds of stem cell transplant from a donor who carried a gene (CCR5?32/?32) that is resistant to HIV, and a chemotherapy drug regimen. The transplant aims to make the virus unable to replicate in the patient’s body by replacing the patient’s immune cells with those of the donors, whilst the body irradiation and chemotherapy targets any residual HIV virus.

The patient reported in this study (the ‘London patient’), underwent one stem-cell transplantation, a reduced-intensity chemotherapy drug regimen, without whole body irradiation. In 2019, it was reported that their HIV was in remission, and this study provides follow-up viral load blood test results at 30-months and a modelling analysis to predict the chances of viral re-emergence.

Ultrasensitive viral load sampling from the London patient’s cerebrospinal fluid, intestinal tissue, or lymphoid tissue was taken at 29 months after interruption of ART and viral load sampling of their blood at 30 months. At 29 months, CD4 cell count (indicators of immune system health and stem cell transplantation success) was measured, and the extent to which the patient’s immune cells have been replaced by those derived from the transplant.

Results showed no active viral infection was detected in samples of the patient’s blood at 30 months, or in their cerebrospinal fluid, semen, intestinal tissue, and lymphoid tissue 29 months after stopping ART.

The patient had a healthy CD4 cell count, suggesting they have recovered well from the transplant, with their CD4 cells replaced by cells derived from the HIV-resistant transplanted stem cells.

Furthermore, 99% of the patient’s immune cells were derived from the donor’s stem cells, indicating the stem-cell transplant had been successful.

Since it was not possible to measure proportion of cells derived from the donor’s stem cells in all parts of the patient’s body (i.e. measurement was not possible in some tissue cells like lymph nodes), the authors used a modelling analysis to predict the probability of cure based on two possible scenarios. If 80% of patient’s cells are derived from the transplant, the probability of cure is predicted at 98%; whereas if they have 90% donor derived cells, they predict a 99% probability of cure.

Comparing to the treatment used on the Berlin patient, the authors highlight that their case study of the London patient represents a step towards a less intensive treatment approach, showing that the long-term remission of HIV can be achieved using reduced intensity drug regimens, with one stem cell transplant (rather than two) and without total body irradiation.

However, being only the second reported patient to undergo this experimental treatment successfully, the authors note that that the London patient will need continued, but much less frequent, monitoring for re-emergence of the virus.

Speculating on what their results might mean for future developments of HIV cures that utilise the CCR5 (HIV resistant) gene, co-author on the study, Dr Dimitra Peppa, University of Oxford, UK, says: “Gene editing using the CCR5 has received a lot of attention recently. The London and Berlin patient are examples of using the CCR5 gene in curative therapies outside of gene editing. There are still many ethical and technical barriers — e.g. gene editing, efficiency and robust safety data — to overcome before any approach using CCR5 gene editing can be considered as a scalable cure strategy for HIV.”

Writing in a linked Comment, lead author Professor Sharon R Lewin, University of Melbourne, Australia, (who was not involved in the study), says, “The finding of no intact virus can be reassuring for a patient who might face significant anxiety and uncertainty about whether and when viral rebound off ART might occur, which in other settings has been completely unpredictable. Given the large number of cells sampled here and the absence of any intact virus, is the London patient truly cured? The additional data provided in this follow up case report is certainly encouraging but unfortunately in the end, only time will tell.”

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Early studies show further applications that could impact donor transplant system — ScienceDaily

A team of researchers at the University of Minnesota Medical School recently proved the ability to grow human-derived blood vessels in a pig — a novel approach that has the potential for providing unlimited human vessels for transplant purposes. Because these vessels were made with patient-derived skin cells, they are less likely to be rejected by the recipient, helping patients potentially avoid the need for life-long, anti-rejection drugs.

Daniel Garry, MD, PhD, and Mary Garry, PhD, both professors in the Department of Medicine at the U of M Medical School, co-led the research team and published their findings in Nature Biotechnology last week.

“There’s so many chronic and terminal diseases, and many people are not able to participate in organ transplantation,” said Daniel, who is also a heart failure and transplant cardiologist. “About 98 percent of people are not going to be eligible for a heart transplant, so there’s been a huge effort in trying to come up with strategies to increase the donor pool. Our approach looked at a pig.”

Because of similarities between human and pig physiology, scientists have historically studied pigs to discover treatments for health issues, including diabetes. Before researchers engineered human insulin, doctors treated patients with pig insulin.

“Our discovery has made a platform for making human blood vessels in a pig,” said Daniel. “This could allow us to make organs with human blood vessels that would be less apt to be rejected and could be used in patients in need of a transplant. That’s what typically causes rejection — the lining of the blood vessels in the organs.”

The blood vessels created by the Garry duo will avoid rejection because of the method by which they are made. The team injects human-induced pluripotent stem cells — taken from mature cells scraped from a patient’s skin and reprogrammed to a stem cell state — into a pig embryo, which is then placed into a surrogate pig. In the future, viable piglets, with blood vessels that will be an exact match to the patient, will ensure a successful transplant and the ability to live without the need for immunosuppression, or anti-rejection, drugs.

“There’s hundreds of thousands of patients that have peripheral artery disease, either because of smoking or diabetes or any number of causes, and they have limb amputations,” Mary said. “These blood vessels would be engineered and could be utilized in these patients to prevent those kinds of life-long handicaps, if you will.”

The first phase of their study, approved by the U of M’s Stem Cell Research Oversight committee, brought the first embryo to a 27-day term. Because of the success of this phase, Daniel and Mary are currently seeking the committee’s approval to advance the research further into the later gestational period.

“We’re trying to take it in a phased approach,” Daniel said. “We want to be sure we address all of the possible issues — whether human cells go where we want them to go.”

“While it is a first phase, there’s pretty solid proof of concept,” Mary said. “We believe that we’ve proven that there’s no off-target effects of these cells, so we’re ready to move forward to later gestational stages.”

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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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