Intermediate embryonic stem cell type could lead to advances in regenerative medicine

A team led by UT Southwestern has derived a new “intermediate” embryonic stem cell type from multiple species that can contribute to chimeras and create precursors to sperm and eggs in a culture dish.

The findings, published online this week in Cell Stem Cell, could lead to a host of advances in basic biology, regenerative medicine, and reproductive technology.

Cells in early embryos have a range of distinct pluripotency programs, all of which endow the cells to create various tissue types in the body, explains study leader Jun Wu, Ph.D., assistant professor of molecular biology.

A wealth of previous research has focused on developing and characterizing “naïve” embryonic stem cells (those about four days post-fertilization in mice) and “primed” epiblast stem cells (about seven days post-fertilization in mice, shortly after the embryo implants into the uterus).

However, says Wu, there’s been little progress in deriving and characterizing pluripotent stem cells (PSCs) that exist between these two stages – largely because researchers have not been able to develop a paradigm for maintaining cells in this intermediate state.

Cells in this state have been thought to possess unique properties: the ability to contribute to intraspecies chimeras (organisms that contain a mix of cells from different individuals of the same species) or interspecies chimeras (organisms that contain a mix of cells from different species) and the ability to differentiate into primordial germ cells in culture, the precursors to sperm and eggs.

For this study, the researchers successfully created intermediate PSCs, which they named “XPSCs” from mice, horses, and humans.

Wu says that these results could eventually lead to an array of advances in both basic and applied research. For example, looking at gene activity in XPSCs from different species and interspecies chimeras could help researchers understand which signatures have been conserved through evolution.

Examining the communication between cells in chimeras may help scientists identify strategies that could be used to accelerate the development of tissues and organs from stem cells used for transplantation.

And using chimera-derived primordial germ cells to create sperm and eggs could aid in preserving endangered animal species and advancing infertility treatments.

These XPSCs have enormous potential. Our study helps open the door to each of these possibilities.”


Jun Wu, PhD, Study Leader and Assistant Professor of Molecular Biology, Virginia Murchison Linthicum Scholar in Medical Research, UT Southwestern Medical Center

Wu notes that developing XPSCs presented a special challenge because the conditions that keep naïve PSCs in a stable state are exactly the opposite of those that stabilize primed PSCs.

While culture conditions for naïve PSCs must activate a WNT cell-signaling pathway and suppress the FGF and TGF-ß pathways, the conditions to maintain primed PSCs must suppress WNT and activate FGF and TGF-ß.

Aiming for the preferred environment for XPSC derivation, Wu and his colleagues placed cells from early mouse embryos into cultures containing chemicals and growth factors that activate all three pathways.

These lab-grown cells were extremely stable in culture and able to multiply

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Development of new stem cell type may lead to advances in regenerative medicine

IMAGE

IMAGE: Drs. Jun Wu, Leqian Yu, Yulei Wei and colleagues isolated a new type of pluripotent stem cell from mice, horses, and humans, named XPSCs, which are capable of generating chimeras…
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Credit: Photo illustration by Leqian Yu

DALLAS – Dec. 3, 2020 – A team led by UT Southwestern has derived a new “intermediate” embryonic stem cell type from multiple species that can contribute to chimeras and create precursors to sperm and eggs in a culture dish.

The findings, published online this week in Cell Stem Cell, could lead to a host of advances in basic biology, regenerative medicine, and reproductive technology.

Cells in early embryos have a range of distinct pluripotency programs, all of which endow the cells to create various tissue types in the body, explains study leader Jun Wu, Ph.D., assistant professor of molecular biology. A wealth of previous research has focused on developing and characterizing “naïve” embryonic stem cells (those about four days post-fertilization in mice) and “primed” epiblast stem cells (about seven days post-fertilization in mice, shortly after the embryo implants into the uterus).

However, says Wu, there’s been little progress in deriving and characterizing pluripotent stem cells (PSCs) that exist between these two stages – largely because researchers have not been able to develop a paradigm for maintaining cells in this intermediate state. Cells in this state have been thought to possess unique properties: the ability to contribute to intraspecies chimeras (organisms that contain a mix of cells from different individuals of the same species) or interspecies chimeras (organisms that contain a mix of cells from different species) and the ability to differentiate into primordial germ cells in culture, the precursors to sperm and eggs.

For this study, the researchers successfully created intermediate PSCs, which they named “XPSCs” from mice, horses, and humans.

Wu says that these results could eventually lead to an array of advances in both basic and applied research. For example, looking at gene activity in XPSCs from different species and interspecies chimeras could help researchers understand which signatures have been conserved through evolution. Examining the communication between cells in chimeras may help scientists identify strategies that could be used to accelerate the development of tissues and organs from stem cells used for transplantation. And using chimera-derived primordial germ cells to create sperm and eggs could aid in preserving endangered animal species and advancing infertility treatments.

“These XPSCs have enormous potential. Our study helps open the door to each of these possibilities,” says Wu, who is a Virginia Murchison Linthicum Scholar in Medical Research.

Wu notes that developing XPSCs presented a special challenge because the conditions that keep naïve PSCs in a stable state are exactly the opposite from those that stabilize primed PSCs. While culture conditions for naïve PSCs must activate a WNT cell-signaling pathway and suppress the FGF and TGF-ß pathways, the conditions to maintain primed PSCs must suppress WNT and activate FGF and TGF-ß.

Aiming for the preferred environment for XPSC derivation, Wu and his

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Baylor College of Medicine gives away STEM kits to teacher

Baylor College of Medicine and Hess Corp. are giving away 1,000 free Hess Toy Truck STEM (science, technology, engineering, mathematics) kits for teachers to use in their classrooms. The kits include 12 of the 2020 Hess Ambulance and Rescue, a pair of first responder toy trucks that can be used with this year’s corresponding STEM curriculum guide.

The 2020 Hess Toy Truck curriculum guide “STEM to the Rescue” uses the Hess Ambulance and Rescue team as a learning tool to teach students the principles of STEM. This is Baylor’s fifth year collaborating with Hess to develop a free curriculum guide that corresponds with Hess’s featured toy truck. The company’s first toy truck was in 1964 and has been a holiday tradition since.

“This partnership shows how universities and corporations can work together and bring the various strengths that they have to provide learning opportunities for students,” said Dr. Nancy Moreno, chair of the Department of Education, Innovation and Technology and director of the Center for Educational Outreach at Baylor.

Hess is accepting applications from teachers through Dec. 31. The kits will be delivered in February to chosen applicants.

Designed by Baylor’s Center for Educational Outreach, the curriculum guide is divided into seven lessons for elementary and middle school students. The activities apply emergency situations that first responders experience to teach various principles of math and science.

“The point of the activities is to apply STEM skills to real life situations,” said Dr. Gregory Vogt, the primary author of the curriculum guide. “Each of the guide’s activities includes a chart that lists specific STEM skills that are employed in the lesson.”

The activities include using the Hess Ambulance to investigate the angles of inclined planes and learning about force and motion with the Hess Rescue truck. Students also learn how to choose the right gear for the rescue team, measure cargo capacity and handle other emergencies like floods or forest fires.

Vogt adds that the curriculum also introduces students to the medical professions and encourages them to learn about how health sciences universities like Baylor College of Medicine prepare future emergency medical professionals.

Teachers can apply for the free STEM kit on the Hess website. The 2020 Hess Ambulance and Rescue team is available for purchase and the curriculum guide is available for free download on the website: https://hesstoytruck.com/stem.

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California Prop 14 may change lives of sick kids, keep taxpayer funding of stem cell therapy research

Three-year-old Ava was constantly sick. Her gums were inflamed, and every time she got a scraped knee, it turned into a dangerous infection.

Her parents, Alicia and Jon Langenhop, were months pregnant with their third child when they learned that Ava’s constellation of symptoms added up to an extremely rare, inherited disorder of the white blood cells, called leukocyte adhesion deficiency-1. Although antibiotics and antivirals could prolong her life, the disease was considered fatal, usually before kindergarten.

Ava’s primary hope, doctors told the Langenhops, was a bone marrow transplant from someone who was a good match, probably a brother or a sister.

Two-year-old Olivia had inherited the same disease as her big sister. She had been hospitalized with infections, too.

The baby in Alicia’s belly would be the girls’ best hope. Since both parents were carriers of the rare genetic mutation, the new baby, a boy, had a 25% chance of inheriting it, too.

Alicia was still in the hospital last October when they found out baby Landon had the mutation. Around the same time, the couple learned of a research trial in California.

Children Ava, Olivia and Landon Langenhop were diagnosed with an extremely rare, inherited disorder of the white blood cells, called leukocyte adhesion deficiency-1. California Proposition 14, a citizen-initiated ballot measure, authorizes bonds continuing stem cell research.
Children Ava, Olivia and Landon Langenhop were diagnosed with an extremely rare, inherited disorder of the white blood cells, called leukocyte adhesion deficiency-1. California Proposition 14, a citizen-initiated ballot measure, authorizes bonds continuing stem cell research.

Doctors would take each child’s blood cells, fix the mutation and return them. It should be a permanent fix, with less risk than a bone marrow transplant because the healthy cells would be their own, so their bodies wouldn’t reject them as foreign.  

The approach had been tried in only one child, though.

This is the type of research reaching patients nearly two decades after President George W. Bush banned federal funding of stem cell research and 16 years after California residents approved a tax increase on themselves to support research.

Proposition 14 on Tuesday’s ballot asks whether Californians want to continue this work, providing $5.5 billion for stem cell research over the next three decades.

In the early 2000s, stem cell research was controversial because it often required the destruction of human embryos. Though embryonic stem cells remain essential for some therapies, in cases such as the Langenhops’, treatment focuses on manipulating a person’s own cells.

Stem cell science has made tremendous progress, but as in most new fields, the pace remains painstakingly slow. Every treatment has to be the subject of years of trial-and-error research, and many scientific hurdles linger. 

Stem cells have been used to treat rare diseases, such as severe combined immunodeficiency, also known as “bubble boy disease,” and they are being tested in more common conditions such as Parkinson’s disease, macular degeneration, Type 1 diabetes and even heart disease.

“Even if a subset of stuff in the pipeline goes all the way, it will change the world for patients who currently don’t have other good options,” said Sean Morrison, a stem cell biologist in Dallas.

“It’s a pivotal time in the field,” said

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Everything you need to know about the $5.5-billion stem cell measure

Scientists are learning more about how to harness stem cells to reverse heart failure, but treatments won't be widely available right away. Above, a stem cell researcher.
Scientists are learning more about how to harness stem cells to reverse heart failure, but treatments won’t be widely available right away. (Dennis Drenner / For The Times)

Proposition 14 would authorize the sale of $5.5 billion in general obligation bonds for the California Institute for Regenerative Medicine, known as CIRM, for stem cell studies and trials.

Here is a rundown of the ballot measure:

The measure

In 2004, voters approved a bond measure to pay for stem cell research.

Now, with the money from that bond running out, supporters of the state’s stem cell agency are asking taxpayers for a new infusion of cash.

With interest, the bond could cost the state $260 million per year, or $7.8 billion over the next 30 years, according to the nonpartisan Legislative Analyst’s Office.

Pro arguments

Proponents of Proposition 14 say the measure will help find new treatments and cures for chronic diseases and conditions, including cancers, spinal cord injuries, Alzheimer’s, Parkinson’s and heart disease. They say the previous bond advanced research and treatments for more than 75 diseases, including two cancer treatments for fatal blood disorders that were approved by the U.S. Food and Drug Administration.

Without new funding to keep the program going, supporters of Proposition 14 say, groundbreaking medical discoveries and lifesaving research will be slowed or stopped.

Anti arguments

Opponents say that the state shouldn’t take on new debt while facing a pandemic-induced deficit and that medical advances attributed to the previous stem cell bond have been overstated. In addition, opponents say CIRM has been hampered by conflicts of interest and too little oversight, neither of which are remedied by the ballot measure.

The campaign to pass the 2004 ballot measure told voters that the bond would save millions of lives and cut healthcare costs by billions. Critics say that’s not been the case to date, although supporters of this year’s measure note that they never intended those results within 16 years. While there is not much organized opposition, some newspaper editorial boards, including those at the Los Angeles Times and San Francisco Chronicle, have opposed it.

Reading list

With Prop. 14, California voters will be asked for more borrowing to keep stem cell research going

Explaining Prop. 14

Times columnist George Skelton assesses Prop. 14

The California stem cell program’s $5.5-billion funding request might be its downfall

California’s stem cell program faces an existential moment — and a chance for reform

When it comes to disease, stem cells are a game-changer, scientists say. This is why

This story originally appeared in Los Angeles Times.

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Billions of Dollars for Stem Cell Research Institute On California’s November Ballot

SACRAMENTO, Calif.—In an election year dominated by a chaotic presidential race and splashy statewide ballot initiative campaigns, Californians are being asked to weigh in on the value of stem cell research—again.

Proposition 14 would authorize the state to borrow $5.5 billion to keep financing the California Institute for Regenerative Medicine (CIRM), currently the second-largest funder of stem cell research in the world. Factoring in interest payments, the measure could cost the state roughly $7.8 billion over about 30 years, according to an estimate from the nonpartisan state Legislative Analyst’s Office.

In 2004, voters approved Proposition 71, a $3 billion bond, to be repaid with interest over 30 years. The measure got the state agency up and running and was designed to seed research.

During that first campaign, voters were told research funded by the measure could lead to cures for cancer, Alzheimer’s and other devastating diseases, and that the state could reap millions in royalties from new treatments.

Yet most of those ambitions remain unfulfilled.

“I think the initial promises were a little optimistic,” said Kevin McCormack, CIRM’s senior director of public communications, about how quickly research would yield cures. “You can’t rush this kind of work.”

So advocates are back after 16 years for more research money, and to increase the size of the state agency.

Stem cells hold great potential for medicine because of their ability to develop into different types of cells in the body, and to repair and renew tissue.

When the first bond measure was adopted in 2004, the George W. Bush administration refused to fund stem cell research at the national level because of opposition to the use of one kind of stem cell: human embryonic stem cells. They derive from fertilized eggs, which has made them controversial among politicians who oppose abortion.

Federal funding resumed in 2009, and thus far this year the National Institutes of Health has spent about $321 million on human embryonic stem cell research.

But advocates for Proposition 14 say the ability to do that research is still tenuous. In September, Republican lawmakers sent a letter to President Donald Trump urging him to cut off those funds once again.

The funding from California’s original bond measure was used to create the new state institute and fund grants to conduct research at California hospitals and universities for diseases such as blood cancer and kidney failure. The money has paid for 90 clinical trials.

A 2019 report from the University of Southern California concluded the center has contributed about $10.7 billion to the California economy, which includes hiring, construction and attracting more research dollars to the state. CIRM funds more than 56,500 jobs, more than half of which are considered high-paying.

Despite the campaign promises, just two treatments developed with some help from CIRM have been approved by the Food and Drug Administration in the past 13 years, one for leukemia and one for scarring of the bone marrow.

But it’s a bit of a stretch for the institute to take

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Colorado governor appeals to residents to stem virus uptick

DENVER (AP) — Gov. Jared Polis on Tuesday appealed to the resolve of residents, rather than new government mandates, to stem what he called an alarming acceleration of new coronavirus cases and hospitalizations in Colorado.

To that end, Polis announced a public awareness campaign, Step Up Colorado, designed to reinforce personal responsibility in mask-wearing, social distancing, getting tested, self-quarantining and other behaviors to stem the virus’s spread.

In a briefing on the pandemic, Polis refused to say new statewide actions are needed and suggested roughly 80% of the pandemic fight comes down to personal decisions. He insisted local health agencies, such as those in Denver and Mesa counties, which are seeing rising numbers of cases, are best prepared to address that increase with residents.

Polis cited Boulder County, where health authorities imposed drastic measures on social gatherings three weeks ago and brought down the number of new cases from 150 per day to 30 per day.


Left unchecked, the upward trends in new confirmed cases and hospitalizations could test hospital intensive-care capacity in December, the Democratic governor said.

The state reported 1,208 new cases on Tuesday and 417 virus hospitalizations. There are roughly 1,800 intensive-care beds statewide for all health emergencies, Polis said. More than three-quarters of those beds were occupied for all reasons over the previous week, the state health department said Monday.

Health officials reported there were nearly 17 positive COVID-19 cases per 100,000 residents Friday, roughly matching the state’s highest recorded rate in April.

More than 2,000 people have died of the virus in Colorado, which has reported more than 80,000 positive cases. The number of cases is probably higher because of a lack of testing and other reasons.

The new coronavirus causes mild or moderate symptoms for most people, but for some, especially older adults and people with existing health problems, it can cause more severe illness or death.

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