Stem Cell Clinic

Hopkins researchers discover newborn rats hold secret to manufacturing human heart cells – Baltimore Sun

Human heart muscle cells can be created in the lab, but researchers have been unable to grow the immature cells to the point where they could be useful.

It's a conundrum that's stumped researchers in regenerative medicine.

"You cannot really use them for regeneration. You cannot even use them for disease models," said Chulan Kwon, a professor at the Johns Hopkins School of Medicine.

But Kwon said he's discovered a solution for the problem in an unlikely place newborn rats and he published a study about his reasearch last month in the journal Cell Reports.

When immature human heart cells are injected into baby rats, they match the rodents' rapid growth cycle and develop fully. These rats act as living incubators, said Dr. David Kass, a Hopkins professor and cardiologist who co-authored the study.

"The biological environment gives you whatever the magic juice is," Kass said. "There were a lot of people looking for this magic juice."

Researchers at the University of Washington, Harvard and Stanford universities and beyond have been working to solve this puzzle fundamental to regenerative medicine.

"Laboratories throughout the world are working on this," said Dr. Richard Lee, a Harvard professor of stem cell and regenerative biology. "We are all very excited that we can make heart cells, but they're heart cells like an infant's heart cells. We want to make heart cells like our patients, who are mostly adults."

Lee said his research team is working to unravel the conditions that stimulate cells to mature inside the body. He praised the Hopkins discovery.

"It's a very nice step forward," Lee said.

Dr. Charles Murry at the University of Washington also has tried to grow the cells to maturity.

"We tried a whole lot of things that didn't work," he said. "Sort of like Edison and the light bulb."

Murry has seen some positive signs when feeding the cells fat instead of sugar.

"But we haven't seen anything that works as well as putting them back into their natural environment, which is back into a heart," he said.

Soon after the late 1990s when researchers isolated embryonic stem cells, people in the field wondered if the process could be used to grow heart muscles in the lab and someday repair the lasting damage from heart attacks and disease. Researchers in 2007 developed methods to modify skin cells to behave as stem cells, and, about five years later, Murry's research team at the University of Washington developed techniques to activate these modified skin cells into early forms of heart muscle cells.

From there researchers have worked to fully develop them into heart cells, a feat that has proven elusive.

Kass, the Hopkins researcher, compares the cell to a car engine. In an undeveloped state, the engine parts are present but scrambled, so the engine doesn't function.

"When you look at a normal heart muscle cell, it's an exquisitely complicated and well organized engine. Every little protein has to be positioned precisely," Kass said. "This doesn't work if they're willy-nilly, oriented randomly and loosely around the cell."

These undeveloped cells have about 1 percent of the pumping force of an adult heart cell, Kwon said.

"The frustrating thing is even if you culture the dish for more than a year," he said, "they're just kind of stuck in embryonic stages."

Around the summer of 2013, he began experimenting with rats. He uses newborn rats engineered to have no immune system. This ensures the pups don't reject the foreign cells. Mouse hearts were too small.

He injects the rat hearts with as many as 200,000 human cells. These human cells are tagged with a protein that glows green or red under fluorescent light. After about a week, the cells remained immature. But after a month, they appeared developed. The researchers tested these cells and found they could contract or beat precisely like an adult heart cell.

The researchers suspect two forces at play: The rats faster life cycle quickens the cells' development. And the rats' biological cues cause the cells to leap the threshold into maturity.

"So the million dollar question would be: What are those cues?" Kwon said.

Their work was published Jan. 10 in Cell Reports, an open-access journal, and they're still trying to pinpoint the cues.

Further discoveries might allow them to replicate the cues in a petri dish and expedite cell growth by avoiding the delicate injections into rat hearts. While promising, their methods remain too small in scale to offer much help to patients. At least, not yet.

"It has to be a bit more practical," Kass said. "If you're injecting things into rat neonates, they're small. So how many cells can you really get in there, and how many can you actually find?"

The abillity to culture larger quantities would allow doctors to test heart medicines on a patients' own cells, furthering the emerging trend of precision medicine.

In 2015, President Barack Obama announced a $215 million precision medicine initiative aimed at developing treatments that consider someone's genes, environment and lifestyle. The grant money funds efforts at the National Institutes of Health and the National Cancer Institute to advance such treatments.

Dr. Roberto Bolli at the University of Louisville School of Medicine sees potential in the rat method for screening patients with different medicines. Doctors could swab the cheek of a particular patient, modify the cheek cells to behave as stem cells, activate them into early heart cells, and inject them into the rats.

Once grown, the cells could be tested with various treatments.

"This would help tremendously to understand the mechanism or these hereditary diseases and also screen for drugs," Bolli said.

The Hopkins researchers are taking steps to produce more mature cells. Kwon said they will try the method with pig hearts, which are larger and can hold more implanted cells.

"If we can really scale this up," he said, "it has a lot of utilities."

tprudente@baltsun.com

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Hopkins researchers discover newborn rats hold secret to manufacturing human heart cells - Baltimore Sun

Regenerative Medicine Has a Bright Future – Healthline

U.S. Army scientists, working with medical technology companies, have successfully tested and used products and techniques that have enabled Army surgeons to replace the severely burned skin of soldiers as well as transplant new hands and even faces.

At Duke University, researchers are studying zebra fish to learn how science and medicine might someday be able to regenerate severed human spinal cords.

These examples one already in practice and the other in the early research stages illustrate the potential that regenerative medicine offers for the future of medical care.

This research aims to go beyond easing the pain of life-threatening illnesses by changing the way diseases affect the body and then eradicating them.

The vast majority of currently available treatments for chronic and/or life-threatening diseases are palliative, Morrie Ruffin, managing director of the Alliance for Regenerative Medicine (ARM), told Healthline.

ARM, based in Washington, D.C., is considered the preeminent global advocate for regenerative and advanced therapies.

Other treatments delay disease progression and the onset of complications associated with the underlying illness, he said. Very few therapies in use today are capable of curing or significantly changing the course of disease.

Regenerative medicine has the unique ability to alter the fundamental mechanisms of disease, and thereby offer treatment options to patients where there is significant unmet medical need.

And it has the potential to address the underlying causes of disease, Ruffin said, representing a new and growing paradigm in human health.

The field encompasses a number of different technologies, including cell, gene, and tissue-based therapies.

Read more: Re-growing teeth and healing wounds without scars

With the Army breakthroughs, government investment was key.

The U.S. Department of Defense (DOD) has invested more than $250 million in regenerative medicine research over the past decade in an effort to make promising technologies available to wounded service members.

Dr. Wendy Dean is medical officer for the Tissue Injury and Regenerative Medicine Project Management Office at the U.S. Army Medical Materiel Development Activity at Fort Detrick, Md., home to the Armys Medical Research and Materiel Command.

Those investments have yielded a stress-shielding surgical bandage, Embrace, to reduce scarring after surgery, Dean told Healthline. The research has also enabled tremendous progress in burn care, allowing surgeons to improve recovery from severe burns with the use of novel skin replacement strategies, such as ReCell spray-on skin, or skin substitutes such as StrataGraft. These skin replacement methods reduce or eliminate the need for donor sites, a frequent request of burn patients.

These revolutionary products were not developed by the Army, Dean said, but were supported with research funding, initially through the Armed Forces Institute of Regenerative Medicine.

The DOD also has invested in hand and face transplantation efforts for service members and civilians whose injuries are so severe that conventional reconstruction is insufficient, she said.

Dean noted that DOD funding has supported 13 hand transplants to date, including a transplant for retired Sgt. Brendan Marrocco in 2012. He was the first service member to survive quadrilateral amputations sustained in combat. The funding also supported eight face transplants.

The Armys goal is to heal those injured in battle.

Regenerative medicine is still young, but it has shown tremendous progress over the last decade, Dean said. Our mission is to make wounded warriors whole by restoring form, function, and appearance. This field offers the best hope to someday fully restore lost tissue with tissue that is structurally, functionally, and aesthetically a perfect match. It may be years before the vision is a widespread reality, but the field is well on its way.

Read more: Regenerative medicine doctor says forget the pills

At Duke University, Kenneth Poss, professor of cell biology, and director of the Regeneration Next initiative, was the senior investigator for a study of spinal cord regeneration in zebra fish.

Those findings were published in November in the journal ScienceDaily.

In my lab, we are researching genetic factors that enable regeneration of tissues such as heart and spinal in nonmammalian animals like zebra fish, Poss told Healthline. A scientist in my lab, Mayssa Mokalled, led a study finding that a gene called connective tissue growth factor [CTGF] is important for spinal cord regeneration in zebra fish after an injury that completely severs the cord.

CTGF is necessary to stimulate cells called glia to form a tissue bridge across the severed parts of the spinal cord an early step in spinal cord regeneration.

Within eight weeks, the scientists found that zebra fish regenerate a severed spinal cord, including nerve cells, and fully reverse their paralysis.

Developing techniques to treat and reverse spinal cord damage, a paralyzing and often fatal injury, is a pressing need in regenerative medicine, Poss said.

Our findings present a step toward understanding which glial cells can be encouraged to help heal the spinal cord, and how to stimulate this activity, he said. This is just the first step in many before the findings could be applied to humans.

Poss is already planning trials with mice that he hopes to start in the next few months. Mice represent an important stage in applying his latest findings, he said.

Read more: Should you store or donate your childs umbilical cord blood?

So, why is regenerative medicine important?

Regenerative medicine seeks ways to re-grow or engineer healthy tissue without the need for transplants, Poss said. On a global scale, theres a tremendous organ shortage, and transplantation is an expensive and nonpermanent solution.

Imagine the number of lives that could be improved if, for example, we could find ways to use the bodys innate healing mechanisms to regenerate heart muscle in patients that are spiraling toward heart failure after a heart attack.

Imagine how many lives could be improved if we could find interventions that restore functional spinal cord tissue and reverse paralysis.

Ruffin of ARM sees a promising future for regenerative medicine.

We will continue to see the development of additional regenerative medicine therapies for a broad number of acute and chronic, inherited and acquired diseases and disorders, he said. Therapies in this area will continue to advance along the regulatory pathway, many of which are entering phase III clinical trials this year.

In fact, in the next two years, we are anticipating a number of U.S. and E.U. approvals in the cell and gene therapy sector, including therapies that address certain types of cancers, debilitating retinal disorders, rare genetic diseases, and autoimmune conditions. We also expect to see sustained investment, which will help fuel growth and product development within this sector.

A number of cell and gene therapies and technology platforms are demonstrating real potential to address areas of significant unmet medical need, Ruffin said.

These include cell therapies for blood cancers and solid tumors; gene therapies for rare genetic diseases as well as chronic conditions; and gene editing for the precise targeting and modification of genetic material of a patients cells to cure a broad range of diseases with a single treatment.

Poss at Duke talked about the ultimate quest.

Regenerative medicine has been most successful in restoring or replacing the hematopoietic tissue that creates blood, he said.

We still lack successful regenerative therapies for most tissues, Poss said. The future of regenerative medicine the holy grail will be stimulating the regeneration of healthy tissue in patients without adding cells or manufactured tissue.

Working out the details of innate mechanisms of regeneration in animals like salamanders, zebra fish, and mice, can inform this approach, he said. So can improvement in factor delivery and genome editing applications to encourage the regeneration of healthy tissue.

Ultimately, Poss said, regenerative medicine will change the toolbox of physicians and surgeons, with major impact on outcomes of diabetes, spinal cord injuries, neurodegenerative disease, and heart failure.

ARM says the public does not realize how far the field has progressed in recent years.

Currently, there are more than 20 regenerative medicine products on the market, Ruffin said, primarily in the therapeutic areas of oncology, musculoskeletal and cardiovascular repair, and wound healing.

More than 800 clinical trials are now underway to evaluate regenerative advanced therapies in a vast array of therapeutic categories, he said.

Were seeing a significant focus on oncology, cardiovascular disease, and neurodegenerative diseases, with more than 60 percent of trials falling into one of these three categories, he added. Even though the majority of people perceive regenerative medicine as something of the future, its actually here and now.

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Regenerative Medicine Has a Bright Future - Healthline

Scientists say new medical diagnostic chip can sort cells anywhere with an inkjet – Wikinews

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Thursday, February 9, 2017

On Monday, scientists from the Stanford University School of Medicine announced the invention of a new diagnostic tool that can sort cells by type: a tiny printable chip that can be manufactured using standard inkjet printers for possibly about one U.S. cent each. Lead researchers say this may bring early detection of cancer, tuberculosis, HIV and malaria to patients in low-income countries, where the survival rates for illnesses such as breast cancer can be half those of richer countries.

Existing methods tend to identify cell types using fluorescent or magnetic labels, which take time to attach, but this platform uses the phenomenon of dielectrophoresis: because different kinds of cells have different levels of receptivity to electrical fields, a trait called polarizability, when an electric potential gradient is activated around the chip, different cells are pulled in different directions at different speeds. This allows doctors to diagnose cancer by determining the number of tumor cells in a patient's blood sample. Different chips can be printed to diagnose different diseases.

Physically, the scientists say, the system has two parts. Cells are held in a clear microfluidic chamber made of silicone. The chip itself is an electronic strip that can be printed onto flexible polyester. Most lab-on-a-chip devices must be manufactured by professional staff in specialized facilities called clean rooms and can take weeks, but the chip component of this system can be made almost anywhere in as little as twenty minutes. The chips cost approximately one U.S. cent to produce (US$0.01) and can be reused. For comparison, a standard flow cytometry machine can cost US$100,000 to purchase.

"Enabling early detection of diseases is one of the greatest opportunities we have for developing effective treatments," said lead author and electrical engineer Dr. Rahim Esfandyarpour. "Maybe $1 in the U.S. doesn't count that much, but somewhere in the developing world, it's a lot of money."

Senior author Dr. Ron Davis of the Stanford University Genome Technology Center compared this invention to that of low-cost genome sequencing, which helped lead to personalized medicine.

The findings appeared in the Proceedings of the National Academy of Sciences on Monday.

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Scientists say new medical diagnostic chip can sort cells anywhere with an inkjet - Wikinews

Scientists identify aggressive pancreatic cancer cells and their vulnerability – Medical Xpress

February 9, 2017 Credit: University of Texas M. D. Anderson Cancer Center

Researchers have identified a gatekeeper protein that prevents pancreatic cancer cells from transitioning into a particularly aggressive cell type and also found therapies capable of thwarting those cells when the gatekeeper is depleted.

A team from The University of Texas MD Anderson Cancer Center describes this week in the journal Nature a series of preclinical experiments using patient-derived tumor xenografts (PDXs) and mouse models that point to potential treatments for patients with a rapidly-progressing and resistant subgroup of tumor cells.

"Pancreatic cancer cells are characterized by remarkable plasticity, cellular changes that make this malignancy so difficult to treat," said first author Giannicola Genovese, M.D., instructor in Genomic Medicine.

Genovese and colleagues found, in a subset of tumor cells, after the original oncogenic driver fades, depletion of a gene called SMARCB1 results in a cellular change to mesenchymal status, a mobile and invasive cell state.

The team also found a vulnerability for mesenchymal cells: they are overly reliant on accelerated protein production to meet increased metabolic needs.

"Inhibiting proteostasis in combination with standard of care chemotherapy was highly effective in killing these most aggressive subpopulations of pancreatic cancer," Genovese said.

Identify, understand tumor cells to kill them

This led the team to look at a drug called AUY922, an inhibitor of heat shock protein 90, which blocks proteostasis - the creation, folding, distribution and degrading of proteins. Both as a single agent and combined with the chemotherapy gemcitabine, AUY922 increased the response rate and lengthened survival of mice whose tumors faithfully recapitulated key features of human pancreatic cancers.

A key challenge in treating cancer stems from molecular and genomic variability of tumor cells, which causes functional differences across cells that can fuel resistance to treatment.

"We are working to dissect the cell populations within tumors to attempt to understand the functional vulnerabilities of each, then to plan for more rational combinatorial treatment approaches," said Giulio Draetta, M.D., Ph.D., professor of Genomic Medicine and director of MD Anderson's Institute for Applied Cancer Science.

Draetta, who is corresponding author of the paper, noted that identifying the subpopulation of aggressive cells and establishing their vulnerability to proteostasis inhibitors allows a match of treatment to specific cell type. "This is truly functionally defined, personalized medicine."

Path to mesenchymal status

To identify and study the impact of pancreatic cancer cell plasticity, the team established an experimental approach to isolate and characterize single cell clones called "escapers" that spontaneously acquire malignant features. They identified two major sub-populations, one preserving simpler epithelial differentiation, one displaying mesenchymal features.

Profiling the two types of escaper populations revealed that mesenchymal clones are characterized by the extinction of KRAS signaling, a common driver of pancreatic cancer, and the abnormal activation of epigenetic programs regulated by the chromatin remodeling factor SMARCB1.

Lower SMARCB1, shorter life

To explore the clinical relevance of these findings, the researchers analyzed surgically removed tumors from 134 patients and identified a subset of patients whose tumors displayed low levels of SMARCB1, independence from KRAS signaling and who had a dismal prognosis.

Subsequent experiments ablating the SMARCB1 gene in mouse models led to the rapid expansion of mesenchymal sub-populations with powerful growth and metastatic characteristics. Restoring SMARCB1 caused mesenchymal cells to revert to the less aggressive epithelial type, establishing SMARCB1 as a gatekeeper of epithelial identity.

The researchers also found that SMARCB1-deficient cells had increased protein synthesis rates and activation of a number of protein-related stress-response pathways. They also found that expression of the oncogene MYC is required to maintain the mesenchymal state in SMARCB1-deficient cells.

To test the stress-response connection, they ablated a crucial stress response gene, which resulted in tumor regression and prolonged survival in mice.

These findings led to the experiments with the HSP90 inhibitor AUY922, which caused tumor cell death and hindered growth in SMARCB1-deficient mice but had a limited impact on mice with intact SMARCB1. The combination with gemcitabine extended survival in mice transplanted with patient-derived xenografts.

Hunting mechanisms of cell change

"This work represents the first step of a major effort to understand the mechanisms allowing malignant cells to hijack specific gene programs to adapt to stress and survive," Genovese said. "Today we have a detailed map of the genetic landscape driving cancer initiation and progression, but our knowledge of the epigenetic, metabolic and molecular programs conferring on tumors cells the ability to change state are still elusive."

The team is developing novel technological tools to dissect those mechanisms in detail and also collaborates with the Institute for Applied Cancer Science to translate its findings by designing tailored clinical trials to exploit the vulnerabilities of those highly aggressive mesenchymal cells.

Explore further: Loss of key protein unleashes cascade that culminates in rhabdoid tumor formation

More information: Giannicola Genovese et al, Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer, Nature (2017). DOI: 10.1038/nature21064

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Scientists identify aggressive pancreatic cancer cells and their vulnerability - Medical Xpress