Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers pinpoint sources of fibrosis-promoting cells that ravage organs

02.07.2013
4 pathways lead to creation of myofibroblasts that cause destructive runaway scarring

Scientists have tracked down and quantified the diverse origins of cells that drive fibrosis, the incurable, runaway wound-healing that scars and ultimately destroys organs such as the lungs, liver and kidneys.

Findings from research conducted at Beth Israel Deaconess Medical Center, Harvard Medical School and Massachusetts Institute of Technology in Boston and continued at The University of Texas MD Anderson Cancer Center are reported in an advance online publication at Nature Medicine on June 30.

"Answering a fundamental question about the origin of these cells by identifying four separate pathways involved in their formation allows us to look at ways to block those pathways to treat fibrosis," said senior author Raghu Kalluri, Ph.D., M.D., MD Anderson chair and professor of Cancer Biology. "It's highly unlikely that a single drug will work."

"In addition to being lethal in its own right, fibrosis is a precursor for the development of cancer and plays a role in progression, metastasis and treatment resistance," Kalluri said. "In some cancers, such as pancreatic cancer, up to 95 percent of tumors consist of fibrotic stroma."

Working in genetic mouse models of kidney fibrosis, Kalluri and colleagues identified four sources of cells called myofibroblasts, the dominant producers of collagen. Collagen normally connects damaged tissue and serves as scaffolding for wound-healing. As healing occurs, myofibroblasts and collagen usually diminish or disappear.

In fibrosis, collagen production marches on. While inflammation-inhibiting drugs can sometimes slow its progress, fibrosis now is treatable only by organ transplant.

Myofibroblasts have four types of parents

The researchers employed a fate-mapping strategy to track cells on their way to becoming myofibroblasts. In fate mapping, the promoter of a protein expresses a color inside a cell that remains with the cell no matter what happens to it until it dies, Kalluri said.

This was particularly important because two of the four sources of myofibroblasts start out as another cell type and differentiate into the collagen-producing cells.

Their experiments showed:

Half of all myofibroblasts are produced by the proliferation of pre-existing resting fibroblasts.

Another 35 percent are produced by mesenchymal stem cells that originate in the bone marrow, migrate to the "wound" site, and then differentiate into myofibroblasts.

An additional 10 percent are the products of endothelial to mesenchymal transition (EndMT), in which blood vessel cells change into mesenchymal cells, then become myofibroblasts.

The final 5 percent come from epithelial to mesenchymal transition (EMT), in which functional cells of an organ sometimes behave like mesenchymal cells and myofibroblasts.

"These differentiation pathways provide leads for drug targets," Kalluri said.
"Combining an antiproliferation drug with therapies that block one or more differentiation pathways could provide a double hit to control fibrosis. We hope to synergize these pathways for the most effective therapeutic response."

Recruitment from the bone marrow, EMT and EndMT appear to rely on transforming growth factor beta 1 (TGF-B1) to differentiate into myofibroblasts.

Pericytes are not involved

Some earlier descriptive studies implicated pericytes – connective, contractile cells that surround blood vessels – in the creation of myofibroblasts. The researchers tested pericytes via fate-mapping and found that they're not involved in myofibroblast generation.

Deleting pericytes did not improve kidney fibrosis or change the recruitment of myofibroblasts.

While their research focused on kidney fibrosis, the scientists believe their findings will be applicable to other types of fibrosis.

"Recruitment of fibroblasts is heterogonous. The sources are likely to be the same for lung or liver fibrosis, but the ratios may be different," Kalluri said. "Now we need to go into those other organs and establish a baseline of what we're facing like we did in kidney fibrosis."

Kalluri holds the Rebecca Meyer Brown and Joseph Mellinger Brown Chair in Basic Science Research and also and directs MD Anderson's Metastasis Research Center.

Co-authors with Kalluri are lead author Valeria LeBleu, Ph.D., and Hikaru Sugimoto, Ph.D., of MD Anderson's Department of Cancer Biology and Metastasis Research Center and formerly of the Department of Matrix Biology at Beth Israel Deaconess Medical Center, the home of co-authors Gangadhar Taduri, M.D., Joyce O'Connell, Ph.D.,Vesselina Cooke, Ph.D., and Craig Woda, M.D.

This research was funded by grants from the National Institutes of Health (DK55001, DK81976, CA125550, CA155370 and CA151925, 2T32DK007760-11, (5T32HL007374-30), the U.S. National Research Service Award F32 Ruth Kirschstein Postdoctoral Fellowship ((5F32DK082119-02) and the U.S. Department of Defense Breast Cancer Predoctoral Traineeship Award.

Scott Merville | EurekAlert!
Further information:
http://www.mdanderson.org

More articles from Health and Medicine:

nachricht Laser activated gold pyramids could deliver drugs, DNA into cells without harm
24.03.2017 | Harvard John A. Paulson School of Engineering and Applied Sciences

nachricht What does congenital Zika syndrome look like?
24.03.2017 | University of California - San Diego

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>