Everything Old Can Get Youth Again?

Old human cells rejuvenated with stem cell technology

Source:     Stanford Medicine
Summary:    Old human cells return to a more youthful and vigorous state after being induced to briefly express a panel of proteins involved in embryonic development, according to a new study.

Stem cells illustration (stock image). | Credit: © nobeastsofierce / stock.adobe.com
Stem cells illustration (stock image).
Credit: © nobeastsofierce / Adobe Stock

Old human cells return to a more youthful and vigorous state after being induced to briefly express a panel of proteins involved in embryonic development, according to a new study by researchers at the Stanford University School of Medicine.

The researchers also found that elderly mice regained youthful strength after their existing muscle stem cells were subjected to the rejuvenating protein treatment and transplanted back into their bodies.

The proteins, known as Yamanaka factors, are commonly used to transform an adult cell into what are known as induced pluripotent stem cells, or iPS cells. Induced pluripotent stem cells can become nearly any type of cell in the body, regardless of the cell from which they originated. They’ve become important in regenerative medicine and drug discovery.

The study found that inducing old human cells in a lab dish to briefly express these proteins rewinds many of the molecular hallmarks of aging and renders the treated cells nearly indistinguishable from their younger counterparts.

“When iPS cells are made from adult cells, they become both youthful and pluripotent,” said Vittorio Sebastiano, PhD, assistant professor of obstetrics and gynecology and the Woods Family Faculty Scholar in Pediatric Translational Medicine. “We’ve wondered for some time if it might be possible to simply rewind the aging clock without inducing pluripotency. Now we’ve found that, by tightly controlling the duration of the exposure to these protein factors, we can promote rejuvenation in multiple human cell types.”

Sebastiano is the senior author of the study, which will be published online March 24 in Nature Communications. Former graduate student Tapash Sarkar, PhD, is the lead author of the article.

“We are very excited about these findings,” said study co-author Thomas Rando, MD, PhD, professor of neurology and neurological sciences and the director of Stanford’s Glenn Center for the Biology of Aging. “My colleagues and I have been pursuing the rejuvenation of tissues since our studies in the early 2000s revealed that systemic factors can make old tissues younger. In 2012, Howard Chang and I proposed the concept of using reprogramming factors to rejuvenate cells and tissues, and it is gratifying to see evidence of success with this approach.” Chang, MD, PhD, is a professor of dermatology and of genetics at Stanford.

Exposure to proteins:        Researchers in Sebastiano’s laboratory make iPS cells from adult cells, such as those that compose skin, by repeatedly exposing them over a period of about two weeks to a panel of proteins important to early embryonic development. They do so by introducing daily, short-lived RNA messages into the adult cells. The RNA messages encode the instructions for making the Yamanaka proteins. Over time, these proteins rewind the cells’ fate — pushing them backward along the developmental timeline until they resemble the young, embryonic-like pluripotent cells from which they originated.

During this process the cells not only shed any memories of their previous identities, but they revert to a younger state. They accomplish this transformation by wiping their DNA clean of the molecular tags that not only differentiate, say, a skin cell from a heart muscle cell, but of other tags that accumulate as a cell ages.

Recently researchers have begun to wonder whether exposing the adult cells to Yamanaka proteins for days rather than weeks could trigger this youthful reversion without inducing full-on pluripotency. In fact, researchers at the Salk Institute for Biological Studies found in 2016 that briefly expressing the four Yamanaka factors in mice with a form of premature aging extended the animals’ life span by about 20%. But it wasn’t clear whether this approach would work in humans.

Sarkar and Sebastiano wondered whether old human cells would respond in a similar fashion, and whether the response would be limited to just a few cell types or generalizable for many tissues. They devised a way to use genetic material called messenger RNA to temporarily express six reprogramming factors — the four Yamanaka factors plus two additional proteins — in human skin and blood vessel cells. Messenger RNA rapidly degrades in cells, allowing the researchers to tightly control the duration of the signal.

The researchers then compared the gene-expression patterns of treated cells and control cells, both obtained from elderly adults, with those of untreated cells from younger people. They found that cells from elderly people exhibited signs of aging reversal after just four days of exposure to the reprogramming factors. Whereas untreated elderly cells expressed higher levels of genes associated with known aging pathways, treated elderly cells more closely resembled younger cells in their patterns of gene expression.

When the researchers studied the patterns of aging-associated chemical tags called methyl groups, which serve as an indicator of a cell’s chronological age, they found that the treated cells appeared to be about 1½ to 3½ years younger on average than untreated cells from elderly people, with peaks of 3½ years (in skin cells) and 7½ years (in cells that line blood vessels).

Comparing hallmarks of aging:    Next they compared several hallmarks of aging — including how cells sense nutrients, metabolize compounds to create energy and dispose of cellular trash — among cells from young people, treated cells from old people and untreated cells from old people.

“We saw a dramatic rejuvenation across all hallmarks but one in all the cell types tested,” Sebastiano said. “But our last and most important experiment was done on muscle stem cells. Although they are naturally endowed with the ability to self-renew, this capacity wanes with age. We wondered, Can we also rejuvenate stem cells and have a long-term effect?”

When the researchers transplanted old mouse muscle stem cells that had been treated back into elderly mice, the animals regained the muscle strength of younger mice, they found.

Finally, the researchers isolated cells from the cartilage of people with and without osteoarthritis. They found that the temporary exposure of the osteoarthritic cells to the reprogramming factors reduced the secretion of inflammatory molecules and improved the cells’ ability to divide and function.

The researchers are now optimizing the panel of reprogramming proteins needed to rejuvenate human cells and are exploring the possibility of treating cells or tissues without removing them from the body.

“Although much more work needs to be done, we are hopeful that we may one day have the opportunity to reboot entire tissues,” Sebastiano said. “But first we want to make sure that this is rigorously tested in the lab and found to be safe.”

Other Stanford co-authors are former postdoctoral scholar Marco Quarta, PhD; postdoctoral scholar Shravani Mukherjee, PhD; graduate student Alex Colville; research assistants Patrick Paine, Linda Doan and Christopher Tran; Constance Chu, MD, professor of orthopaedic surgery; Stanley Qi, PhD, assistant professor of bioengineering and of chemical and systems biology; and Nidhi Bhutani, PhD, associate professor of orthopaedic surgery.

Researchers from the Veterans Affairs Palo Alto Health Care System, the University of California-Los Angeles and the Molecular Medicine Research Institute in Sunnyvale, California, also contributed to the study.

The research was supported by the National Institutes of Health (grants R01 AR070865, R01 AR070864, P01 AG036695, R01 AG23806, R01 AG057433 and R01 AG047820), the Glenn Foundation for Medical Research, the American Federation for Aging Research and the Department of Veterans Affairs.

Sarkar, Quarta and Sebastiano are co-founders of the startup Turn Biotechnologies, a company that is applying the technology described in the paper to treat aging-associated conditions. Rando is a member of the scientific advisory board.


Story Source::    Materials provided by Stanford Medicine. Original written by Krista Conger. Note: Content may be edited for style and length.


Journal Reference:

  1. Tapash Jay Sarkar, Marco Quarta, Shravani Mukherjee, Alex Colville, Patrick Paine, Linda Doan, Christopher M. Tran, Constance R. Chu, Steve Horvath, Lei S. Qi, Nidhi Bhutani, Thomas A. Rando, Vittorio Sebastiano. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nature Communications, 2020; 11 (1) DOI: 10.1038/s41467-020-15174-3

Cite This Page:

Stanford Medicine. “Old human cells rejuvenated with stem cell technology.” ScienceDaily. ScienceDaily, 24 March 2020. <www.sciencedaily.com/releases/2020/03/200324090007.htm>.
from:    https://www.sciencedaily.com/releases/2020/03/200324090007.htm

And Now GM Babies

image: http://www.redorbit.com/media/uploads/2016/02/ThinkstockPhotos-521744495.jpg

human embryos

February 1, 2016

UK scientists receive approval to modify human embryos

Less than one year after Chinese researchers revealed that they had genetically modified human embryos, scientists at the Francis Crick Institute in London have gotten the go-ahead to conduct similar experiments, officials at the medical research facility revealed on Monday.

According to Reuters and BBC News, Dr. Kathy Niakan, a stem cell researcher at the Institute, said she and her colleagues had been granted a license to conduct their experiments from the Human Fertilization and Embryology Authority (HFEA), the division of the UK’s Department of Health that regulates fertility clinics and regulates research involving embryos.

Dr. Niakan’s laboratory told reporters that the research would attempt to shed new light into the first moments of human life, and that they would be banned from implanting modified embryos into a woman. Nonetheless, the research is causing concern among some that it could eventually lead to genetically engineered “designer” babies.David King, director of the UK watchdog Human Genetics Alert, told Reuters that the move was “the first step on a path… toward the legalization of GM babies,” while Dr. Sarah Chan from the University of Edinburgh told BBC News that although such research “touches on some sensitive issues… its ethical implications [had] been carefully considered by the HFEA.”

Experiments will involve recently-fertilized eggs

Reports indicate that the experiments will use CRISPR-Cas9, technology that can identify and correct genetic defects. It is to be conducted during the first seven days following fertilization, a period in which the fertilized egg develops from a single cell into a blastocyst containing 200 to 300 cells.

Once a fertilized egg reaches the blastocyst stage, some of its cells have been organized to play specific roles – forming the placenta or the yolk sac, for example. Some parts of our DNA tend to be very active at this stage in human development, the researchers said, and it is believed that some of these genes play a key role in guiding our early growth.

How and why these processes take place remains a mystery, and experts are uncertain what they are going and what might go wrong genetically prior to a miscarriage. Dr. Niakan, who has been researching human development for more than a decade, will look to modify these genes during their experiments, and will only be using donated embryos, according to BBC News.

HFEA said that experiments could start within the next several months, and Paul Nurse, director of the Crick Institute, said that he was “delighted” that their application had been approved, and that Dr Niakan’s research would be “important for understanding how a healthy human embryo develops and will enhance our understanding of IVF success rates.”

“This project, by increasing our understanding of how the early human embryo develops and grows, will add to the basic scientific knowledge needed for devising strategies to assist infertile couples and reduce the anguish of miscarriage,” said Bruce Whitelaw, an animal biotechnology professor at Edinburgh University’s Roslin Institute. He added that the approval was granted “after robust assessment” of the proposed experiments.

Read more at http://www.redorbit.com/news/health/1113412324/uk-scientists-receive-approval-to-modify-human-embryos-020116/#KozxSQibt8m8tv6o.99

Growing New Teeth from Stem Cells

Science with real bite: Full set of teeth grown in the lab

By FIONA MACRAE

Last updated at 5:26 PM on 13th July 2011

Scientists have grown fully formed teeth from stem cells.

The artificial teeth looked like the real thing, were sensitive to pain and could chew food.

The breakthrough was made on mice but could pave the way for those who lose teeth to decay or injury being able to ‘grow’ replacements.

Cutting edge: A bioengineered tooth, bottom right, successfully transplanted into the jaw of a mouseCutting edge: A bioengineered tooth, bottom right, successfully transplanted into the jaw of a mouse

The researchers harnessed the power of stem cells – ‘master cells’ which have the potential to be used to grow any part of the body – to generate teeth.

Two types of stem cell which between them contain all the instructions for making teeth were mixed together and grown in the lab in a mixture of chemicals and vitamins that started their transformation.

Read more: http://www.dailymail.co.uk/sciencetech/article-2014076/Science-real-bite-Full-set-teeth-grown-lab.html#ixzz1UdpLe8GW