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The Cutting Edge

Researchers Create Accurate Model of Organ Scarring

Researchers Create Accurate Model of Organ Scarring

Microscopic image of scarring in a dish, showing evidence of fibrosis (red, green) and nuclei of all cells (blue). Image: Courtesy of UCLA Broad Stem Cell Research Center/Cell Reports

While every organ in the body is capable, to some extent, of repairing itself after an injury, the process creates scar tissue that, under some circumstances, can go rogue and continuously divide and spread until it strangles the organ it was intended to help heal. That progressive, out-of-control scarring, which can lead to organ failure, is called fibrosis. Fibrosis plays a major role in many diseases and conditions, including chronic kidney disease, liver cirrhosis, idiopathic pulmonary fibrosis, scleroderma and heart failure.

For decades, researchers have sought a therapy that can halt or reverse fibrosis, but replicating the complex, progressive nature of the disease in the lab has been problematic. A team led by Brigitte Gomperts, MD, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and the UCLA Jonsson Comprehensive Cancer Center, now has developed a “scar in a dish” model that uses multiple types of cells derived from human stem cells to closely mimic the progressive scarring that occurs in human organs. The researchers used this model to identify a drug candidate that stopped the progression of and even reversed fibrosis in animal models.

Brigitte N. Gomperts, MD

Brigitte N. Gomperts, MD

The model was created using induced pluripotent stem cells, which can generate any cell type. The resulting mixture contained many types of cells that are thought to play a role in fibrosis. All of the cells in the mixture retained a degree of plasticity, meaning they had the capacity to change cell types, from an epithelial cell to a mesenchymal cell, for example.

The cell mixture then was introduced to a rigid hydrogel that recreated the approximate stiffness of a scarred organ. The cells responded in the same way that they respond to injury in the body, by producing signals of injury or damage and activating a molecule called transforming growth factor beta, or TGF beta, which serves as the spark that sets off the roaring fire of fibrosis.

In the past, researchers in the lab used one type of cell to which they added TGF beta to provoke scarring. But those experiments produced models that tended to heal on their own, which made it difficult to discern whether possible treatments were working or the model was simply “healing” itself. By using the hydrogel to simulate injury and provoke TGF beta production, Dr. Gomperts’ team ensured their model was not able to heal itself; as long as the cells remained on the hydrogel, they perceived an “injury” and continued to progressively scar. That gave the researchers the opportunity to test drug candidates on a scar that wasn’t actively engaged in healing itself.

The team then set out to identify drugs that could halt or reverse the process. After testing more than 17,000 small molecules — organic compounds that are often used to create pharmaceutical drugs — they identified a small molecule that stopped progressive scarring and even healed the damage it had caused. The researchers suspect the molecule works by activating the cells’ inherent wound-healing processes.

— Tiare Dunlap

 

“Modeling Progressive Fibrosis with Pluripotent Stem Cells Identifies an Anti-fibrotic Small Molecule,” Cell Reports, December 10, 2019


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Winter 2020

Winter 2020
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IN THIS ISSUE
  • Lessons from Sherm
  • Father’s X Chromosome May Yield Clues to Higher Rates of Autoimmune Disease in Women
  • Researchers Create Accurate Model of Organ Scarring
  • Biomarker Predicts Which Heart-failure Patients at Higher Risk of Death within One-to-three Years
  • Targeted Therapy Drug Extends Lives of Women with Aggressive Breast Cancer
  • Can a “Battery Leak” Trigger the Onset of Type 2 Diabetes?
  • Molecular Changes in Cells of Eye’s Lens Predict Future Cataracts
  • UCLA Addresses Increasing Demand with New Master’s in Genetic Counseling
  • Truth Seeker
  • Sherm
  • Repairing and Reversing Damage Caused by Huntington’s Disease
  • Cells’ Mitochondria Work Much Like Tesla Battery Packs
  • The Who and Friends Rock Private Show for UCLA Health and Teen Cancer America
  • A Confounding Case
  • Body Image Concerns Are Universal
  • “We Do Better with Diversity”
  • Annual UCLA Health System Board Meeting Turns Its Focus to Cardiac Care
  • UCLA Operation Mend Cheered on at New York City Veterans Day Parade
  • A Decade in Review: 7 Exciting Health Care Breakthroughs
  • MRI May Help Doctors Differentiate Causes of Memory Loss
  • On the Road to Health Care Equality
  • Learning To Listen
  • Photo Synthesis
  • Awards & Honors
  • In Memoriam
  • David Geffen Adds $46 Million to Landmark Medical Scholarships Program
  • Nearly 2,000 Guests Attend Party on the Pier for UCLA Mattel Children’s Hospital
  • Golden Visionary Ball Raises More than $1 Million for UCLA Neurosurgery
  • Dr. Hans Gritsch Named Inaugural Chair in Kidney Transplantation
  • Nonprofit Heart of the Brain Fuels the Fight against Brain Cancer
  • UCLA Supporters Raise Money for Duchenne Muscular Dystrophy
  • Dancing for NED Fundraiser Fights Ovarian Cancer
  • Gifts
  • In Memoriam
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