Cincinnati, OH, U.S.A.- Researchers have rejuvenated aged hematopoietic stem cells to be functionally younger, offering intriguing clues into how medicine might one day fend off some of the ailments of old age.

Scientists at Cincinnati Children‘s Hospital Medical Center and the Ulm University Medicine in Germany report their findings online May 3 in the journal Cell Stem Cell. The paper brings new perspective to what has been a life science controversy – countering what used to be broad consensus that the aging of hematopoietic stem cells (HSCs) was locked in by nature and not reversible by therapeutic intervention.

HSCs are stem cells that originate in the bone marrow and generate all of the body’s red and white blood cells and platelets. They are an essential support mechanism of blood cells and the immune system. As humans and other species age, HSCs become more numerous but less effective at regenerating blood cells and immune cells. This makes older people more susceptible to infections and disease, including leukemia.

Researchers in the current study determined a protein that regulates cell signaling – Cdc42 – also controls a molecular process that causes HSCs from mice to age. Pharmacologic inhibition of Cdc42 reversed HSC aging and restored function similar to that of younger stem cells, explained Hartmut Geiger, PhD, the study’s principal investigator and a researcher in the Division of Experimental Hematology/Cancer Biology at Cincinnati Children’s, and the Department of Dermatology and Allergic Diseases, Ulm University Medicine.

“Aging is interesting, in part because we still don’t understand how we age,” Geiger said. “Our findings suggest a novel and important role for Cdc42 and identify its activity as a target for ameliorating natural HSC aging. We know the aging of HSCs reduces in part the response of the immune system response in older people, which contributes to diseases such as anemia, and may be the cause of tissue attrition in certain systems of the body.”

The findings are early and involve laboratory manipulation of mouse cells, so it remains to be seen what direct application they may have for humans. Still, the study expands what is known about the basic molecular and cellular mechanisms of aging – a necessary step to one day designing rational approaches to aiding a healthy aging process.

One reason the research team focused on Cdc42 is that previous studies have reported elevated activity of the protein in various tissue types of older mice – which have a natural life span of around two years. Also, elevated expression of Cdc42 has been found in immune system white blood cells in older humans.

In the current study, researchers found elevated activity of Cdc42 in the HSCs of older mice. They also were able to induce premature aging of HSCs in mice by genetically increasing Cdc42 activity in the cells. The aged cells lost structural organization and polarity, resulting in improper placement and spacing of components inside the cells. This disorganization contributed to the cells’ decreased functional efficiency.

The researchers then analyzed HSCs from older mice to see if inhibition of Cdc42 would reverse the aging process. They used a specific dose (5uM) of a pharmacologic inhibitor of Cdc42, CASIN, to reduce the protein’s activity in the cells – processing them for 16 hours ex vivo in laboratory cultures. This improved structural organization, increased polarity and restored functionality in the older cells to levels found in young cells.

To test the rejuvenated cells, the researchers used a process known as serial competitive transplantation. This included extracting HSCs from young (2-4 months) and aged (20-26 months) mice and processing them in laboratory cultures. Young and rejuvenated cells were then engrafted into recipient mice. This allowed scientists to compare how well young and rejuvenated aged HSCs started to repopulate and transform into different types of blood cells. It also confirmed that HSCs rejuvenated by targeting Cdc42 do function similarly to young stem cells.

Researchers next plan to test the Cdc42 inhibitor, CASIN, in mice to see how HSCs and various tissues in the laboratory models respond. In particular, they are testing red blood cell production, endurance and immune response in the mice. The research team is also acquiring samples of human HSCs to see how those cells respond in laboratory tests to Cdc42 expression.

The first author on the study was Maria Carolina Florian, PhD, from the University of Ulm. Also collaborating were Karin Doerr, Anja Niebel, Deidre Daria, Hubert Schrezenmeier, MD, PhD, Markus Rojewski and Karin Sharffetter-Kochanek, all from the University of Ulm, and Yi Zheng, PhD, and Marie-Dominique Filippi, PhD, of Cincinnati Children’s.

Funding support for the research came from the Deutsche Forschungsgemeinschaft and the National Institutes of Health.

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Undercover video footage exposing animal abuse and suffering inside Hawkeye Sow Centers (HSC), a pig breeding factory farm in Leland, Iowa, is being released on February 15 by animal protection organization Compassion Over Killing (COK). The video was filmed by a COK investigator who worked at the facility in December 2011 and wore a hidden camera to document the day-to-day miseries forced upon thousands of female pigs and their piglets.

Iowa is the largest pork-producing state in the U.S., and agribusiness interests are currently trying to pass an “ag-gag” law (HR-589/SF-431) in the state to effectively make whistleblowing exposes on factory farms, like this investigation, illegal.  COK’s video exposes standard industry practices that the industry is desperately trying to hide, including:

• Pregnant and nursing pigs nearly immobilized in tiny crates, unable to even turn around
• Piglets screaming while workers slice off their tails and cut out the males’ genitals without any pain relief
• Poorly performed castrations that resulted in herniated intestines
• Workers pushing the herniated intestines back inside the piglets, then wrapping the area with tape
• Countless sick or injured piglets left to suffer without veterinary care, many of whom later died
• Forced cannibalism: intestines from dead piglets are turned into “gruel” to feed back to pigs
• Layers of feces caked on the floor of crates and  filthy, fly-infested conditions

As our investigator was told, many of the piglets born at this facility will end up on store shelves under the brand name, Hormel. While Hormel recently issued a statement that its company-owned facilities will be phasing out gestation crates, it did not commit to extending this welfare policy to the hundreds of independently-run facilities that ultimately supply Hormel, like HSC, which comprise the majority of Hormel’s pork.

With the news this week that McDonald’s—one of the biggest buyers of pork in the U.S.—is moving to end gestation crate confinement of pigs in its U.S. supply chain, the writing for this inhumane practice is on the wall. It’s time for Hormel for end the use of cruel gestation crates in its entire supply chain.

There’s also no disputing that without anesthesia, male piglets endure immense pain when their testicles are ripped from their bodies. Welfare concerns have prompted Switzerland and Norway to ban this barbaric process, and many other countries have implemented alternatives—alternatives which are also available in the U.S. and should immediately implemented by the pork industry here as well.

“When it comes to the meat industry, animal cruelty is standard practice,” says COK’s executive director Erica Meier. “And rather than try to prevent the worst abuses, Big Agribusiness is trying to prevent Americans from finding out about them with ag-gag bills designed to ban these exposes.

The most effective way consumers can stand up for animals and help stop the cruelty is to simply leave pigs, and all animals, off our plates.

For more information, including investigative footage and photos, visit http://www.cok.net/camp/inv/iowapigs.

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