Navigation Links
Researchers pinpoint sources of fibrosis-promoting cells that ravage organs
Date:7/1/2013

HOUSTON 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.


'/>"/>

Contact: Scott Merville
smerville@mdanderson.org
713-792-0655
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

Related medicine news :

1. Researchers use immunocytochemistry to determine ALK status
2. Researchers find 2 new methods to determine ALK status
3. CWRU researchers trace inner-city womens health issues to childhood traumas
4. Penn Medicine researchers discover link between fear and sound perception
5. UCI researchers awarded $2.27 million to create novel diabetes treatments
6. MS researchers determine that brain reserve independently protects against cognitive decline in MS
7. Notre Dame and Harper researchers developing novel method to test for HPV and oral cancers
8. PhD Thesis Writing Expands the Scope of its Services for Doctoral Researchers
9. Researchers Identify New Genes Linked to the Origins of Alzheimer’s, Says Cure Alzheimers Fund
10. Researchers identify master coordinator for aortic rupture
11. Fate of the heart: Researchers track cellular events leading to cardiac regeneration
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:12/6/2019)... ... December 06, 2019 , ... Allegheny Health Network (AHN) has named ... joined AHN from WVU Medicine in May 2018, previously served as AHN’s Vice Chair ... interim chair since October and is also part of the pathology faculty at Drexel ...
(Date:12/6/2019)... ... December 06, 2019 , ... Dr. Scott Howell, a 2019 graduate of Trident ... the health benefits of coconut oil in the 7 November 2019 edition of ... Cardiometabolic Profile: A Structured Literature Review,” led by Dr. Hector O. Santos, examines the ...
(Date:12/5/2019)... ... December 05, 2019 , ... ... ranging from launching exceptional products that help people embrace, achieve, and maintain a ... “We’ve never been more committed to our mission of impacting world health, so ...
(Date:12/4/2019)... ... December 04, 2019 , ... Healthcare Real ... the only national awards dedicated to recognizing excellence in the areas of healthcare ... presented in nine different categories during the GlobeSt Healthcare Conference today in Scottsdale, ...
(Date:12/2/2019)... ... December 02, 2019 , ... TrialScope, the global leader ... the North American branch of the healthcare business of Merck KGaA, Darmstadt, Germany, ... educate and inform patients, caregivers, the public, patient advocacy groups and healthcare professionals ...
Breaking Medicine News(10 mins):
(Date:12/6/2019)... ... December 06, 2019 , ... ... of treatments for psychiatric and neurodegenerative disorders, announced today that the U.S. Food ... NBTX-001 Inhaler, allowing the Company to initiate its Phase 2b trial for the ...
(Date:12/5/2019)... ... December 05, 2019 , ... ... entrance into the Amazon Web Services (AWS) Public Sector Partner Program; a ... Public Sector Partner program recognizes and collaborates with partners that offer solutions ...
(Date:12/4/2019)... ... December 04, 2019 , ... Tenex ... minimally invasive technologies to treat chronic pain in soft and hard tissue, recently ... TX® technology. , Dr. Bernard Morrey, Chief Medical Officer of Tenex ...
Breaking Medicine Technology: