Telomerase-expressing liver cells regenerate the organ 텔로머레이스 줄기 간세포가 손상된 간 재생

I read a lot of the latest science news and there is more that I do not understand yet.

Perhaps it is more a way for me to learn to understand and summarize a new term than to understand it. 

A subset of liver cells with high levels of telomerase renews the organ during normal cell turnover and after injury, according to Stanford researchers. The cells may also give rise to liver cancer.

Telomerase is a reverse transcriptase enzyme that carries its own RNA molecule which is used as a template when it elongates telomeres. 

It is a bit difficult to understand this article for me, so I have to study telomere and telomerase more.

나는 많은 최신 과학 뉴스를 읽고도 아직은 이해가지 않는게 더 많다.
일고 이해한다기보다는 아마도 새로운 용어를 익히고 이해하고 요점정리하는게 내가 공부할수 있는 방법인것 같다.

스탠퍼드 의과대학 연구진이 노화 관련 효소인 '텔로머레이스' 발현 수준이 높은 간 줄기세포가 손상을 입은 간을 재생시킨다는 사실을 발견했다고 한다.

텔로머레이스는 염색체의 말단에 반복염기서열 구조인 텔로미어를 신장시키는 효소이다.

이 기사를 이해하기 조금 어려워서 텔로미어와 텔로머레이스를 좀더 공부해봐야겠다.

Liver stem cells that express high levels of telomerase, a protein often associated with resistance to aging, act in mice to regenerate the organ during normal cellular turnover or tissue damage, according to a study by researchers at the Stanford University School of Medicine.

The cells are distributed throughout the liver’s lobes, enabling it to quickly repair itself regardless of the location of the damage.

Understanding the liver’s remarkable capacity for repair and regeneration is a key step in understanding what happens when the organ ceases to function properly, such as in cases of cirrhosis or liver cancer.

“The liver is a very important source of human disease,” said professor of medicine Steven Artandi, MD, PhD. “It’s critical to understand the cellular mechanism by which the liver renews itself. We’ve found that these rare, proliferating cells are spread throughout the organ, and that they are necessary to enable the liver to replace damaged cells. We believe that it is also likely that these cells could give rise to liver cancers when their regulation goes awry.”

Artandi is the senior author of the study, which was published online April 4 in Nature. Postdoctoral scholar Shengda Lin, PhD, is the lead author of the article.

스티븐 아탄디(Steven Artandi) 스탠퍼드 의과대학 교수팀은 텔로머레이스의 발현 수준이 높은 간 줄기세포가 쥐의 손상된 장기를 재생시키는 것을 확인했다고 국제학술지 '네이처' 2018년 4월 4일자 온라인판에 발표했다.

아탄디 교수는 "간이 스스로를 재생하는 세포 메커니즘을 이해하는 것은 매우 중요하다"며 "우리는 이 희귀한 세포들이 간에 퍼져 있으며, 손상된 세포를 대체하는 역할을 하는 것을 발견했다"고 전했고 "이 세포들이 제대로 통제되지 않을 경우 간암을 일으킬 수 있다고 생각한다"고 한다.

간이 손상을 입으면 붉은색으로 표현된 세포들이 클론을 증식시켜 죽은 세포들의 자리를 대체한다. 노화 저항성과 연관이 있는 것으로 알려진 단백질 '텔로머레이스'가 높은 수준으로 발현되는 일부 줄기세포가 손상된 간을 재생시키는 역할을 한다는 연구결과가 나왔다.

Liver cells expressing high levels of telomerase (red) proliferate as clones against a background of low-telomerase-expressing cells (blue) during normal liver regeneration.

높은 수준의 텔로머레이스(붉은색)를 발현하는 간 세포와 텔로머레이스가 낮은 수준으로 발현하는 일반 세포(파란색)의 이미지. 

A unique organ

The liver’s cells, called hepatocytes, work to filter and remove toxins from the blood. The liver is unique among organs in its ability to fully regenerate from as little as 25 percent of its original mass. Chronic alcoholism or hepatitis infection can cause cycles of damage and renewal that lead to irreversible scarring that impairs the organ’s function. But relatively little is known about how the organ regenerates, or which cells might be responsible for cancers.

“About 900,000 people die every year worldwide from cirrhosis,” Artandi said, “and liver cancer is the fifth-leading cause of cancer death in the United States. But our understanding of how the liver renews itself has languished in comparison to advances made in other organs.”

간은 혈액에서 독소를 걸러내고 제거하는 역할을 한다. 간은 매우 독특한 장기인데, 전체의 25% 정도만 남아있으면 다시 완전히 재생할 수 있는 능력이 있다. 다만 만성 알코올 중독이나 간염 등으로 인해 돌이킬 수 없는 상처를 입으면 기능을 잃어버리게 된다. 세계적으로 간 조직이 딱딱하게 변해 간 기능이 떨어지는 간경변으로 매년 90만 명이 사망하고, 미국에선 간암이 전체 암으로 인한 사망 원인 중 다섯번째로 꼽힌다. 하지만 아직 간이장기를 재생하는 방법이나 암을 일으키는 세포에 대한 지식은 많지 않은 편이다.

However, stem cells and some cancer cells make enough telomerase to keep their telomeres from shortening, effectively stopping the aging clock and allowing a seemingly unlimited number of cell divisions. Mutations that block telomerase activity cause cirrhosis in mice and humans. Conversely, mutations that kick telomerase into high gear are frequently found in liver cancers. Telomerase is a protein complex that “tops off” the ends of chromosomes after DNA replication. Without its activity, protective chromosomal caps called telomeres would gradually shorten with each cell division. Most adult cells have little to no telomerase activity, and the progressive shortening of their telomeres serves as a kind of molecular clock that limits the cells’ — and, some believe, an organism’s — life span.

텔로머레이스는 염색체 말단 부분인 '텔로미어'를 복구하는 효소로 보통 텔로미어가 짧아질수록 세포가 노화하고, 텔로미어가 사라지면 세포도 사멸하는 것으로 알려져 있다. 

반면 암세포는 텔로머레이스를 과다 분비해 사멸하지 않고 끊임없이 분열을 일으킨다. 이번 연구에서 텔로머레이스의 활성을 차단한 돌연변이 생쥐는 간경변이 유발되는 것으로 나타났다. 반대로 텔로머레이스의 활성을 높인 쥐에게서는 높은 비율로 간암이 발병됐다.

Lin and Artandi wondered whether they could use telomerase expression as a marker to identify the subset of cells responsible for regenerating the liver during normal turnover. These cells, they believe, could also serve as the cell of origin for liver cancer.

Making new cells

Lin found that, in mice, about 3-5 percent of all liver cells express unusually high levels of telomerase. The cells, which also expressed lower levels of genes involved in normal cellular metabolism, were evenly distributed throughout the liver’s lobules. During regular cell turnover or after the liver was damaged, these cells proliferate in place to make clumps of new liver cells.

“These rare cells can be activated to divide and form clones throughout the liver,” said Artandi, who holds the Jerome and Daisy Low Gilbert Professorship in Biochemistry. “As mature hepatocytes die off, these clones replace the liver mass. But they are working in place; they are not being recruited away to other places in the liver. This may explain how the liver can quickly repair damage regardless of where it occurs in the organ.”

연구진은 실험을 통해 텔로미어의 활성 수준이 간 세포의 재생 능력을 확인하는 지표로 활용될 수 있을지, 이 세포들이 간암을 일으키는 원인 세포가 될 수 있는지를 확인했다. 이번 실험에서 모든 쥐들의 간세포에서 3∼5% 정도는 텔로머레이스가 비정상적으로 높은 수준으로 발현하는 것으로 나타났다. 이 세포들은 균등하게 간엽 전체에 분포해있었고, 간이 손상을 입으면 빠르게 클론을 확산해 새로운 간 세포 무리를 만들고 해당 부위를 대체했다.

The fact that these stem cells express fewer metabolic genes might be one way to protect the cells from the daily grind faced by their peers, and to limit the production of metabolic byproducts that can damage DNA.

“This may be one way to shelter these important cells and allow them to pass on a more pristine genome to their daughter cells,” Artandi said. “They are not doing all the ‘worker bee’ functions of normal hepatocytes.”

When Lin engineered the telomerase-expressing hepatocytes to die in response to a chemical signal and gave the mice with a liver-damaging chemical, he found that those animals in which the telomerase cells had been killed exhibited much more severe liver scarring than those in which the cells were functional.

“You could imagine developing drugs that protect these telomerase-expressing cells, or ways to use cell therapy approaches to renew livers,” said Artandi. “On the cancer side, I think that these cells are very strong candidates for cell of origin. We are finally beginning to understand how this organ works.”

이 줄기세포들은 다른 보통 간 세포가 하는 모든 일을 하진 않았다. 이들이 다른 간세포보다 적은 대사 유전자를 발현한다는 사실은 중요한 세포를 보호하고 DNA를 손상시킬 수 있는 대사 부산물 생산을 제한해 더 깨끗한 유전체를 전달하는 방법 중 하나로 추정된다.

아탄디 교수는 "이런 텔로머레이스를 발현하는 세포를 보호하는 약물을 개발하거나 세포 치료법으로 사용해 간을 재생하는 방법을 찾을 수 있을 것"이라고 말했다.

Other Stanford authors are postdoctoral scholars Chandresh Gajera, PhD, Elisabete Nascimento, PhD, Lu Chen, PhD, and Patrick Neuhoefer, PhD; graduate student Alina Garbuzov; and assistant professor of ophthalmology Sui Wang, PhD.

The research was supported by the National Institutes of Health (grants CA197563 and AG056575), the Emerson Foundation and the California Tobacco-Related Disease Research Program.

Artandi is a member of Stanford Bio-X, the Stanford Cancer Institute and the Stanford Child Research Institute.

Stanford’s Department of Medicine also supported the work.

📝 Story :  Krista Conger 

Krista Conger is a science writer for the medical school's Office of Communication & Public Affairs. Email her at kristac@stanford.edu. 

http://med.stanford.edu/news/all-news/2018/04/telomerase-expressing-liver-cells-regenerate-the-organ.html