Tag Archives: #pulmonaryfibrosis

Microgel Coating Gives Donor Cells A Boost in Reversing Pulmonary Fibrosis (Medicine)

Researchers at the University of Illinois Chicago have shown that even after lung tissue has been damaged, it may be possible to reverse fibrosis and promote tissue repair through treatment with microgel-coated mesenchymal stromal cells.

Pulmonary fibrosis is a chronic disease caused by environmental toxins, medications or medical conditions like pneumonia and rheumatoid arthritis. It is characterized by the formation of scar tissue due to damage or an unchecked immune response, and it can cause mild to severe difficulty breathing and oxygen deprivation. Fibrosis is currently thought to be mostly irreversible, as current drug treatments are only mildly effective at managing symptoms and generally cause significant side effects.

Mesenchymal stromal cells, or MSCs, are multipotent and self-renewing, much like stem cells, and they have been studied for their potential to treat conditions like fibrosis.

“While previous studies tested the therapeutic effects of MSCs – which are known to suppress inflammation and to adapt to different tissue environments – their efficacy has so far been limited to early phases of the disease, when inflammation levels are high and scar tissue is still forming,” said Jae-Won Shin, UIC assistant professor of pharmacology and bioengineering at the College of Medicine and corresponding author of the study. “Our approach was to optimize MSC-based therapeutics to work after inflammation has been reduced, which is when most people are diagnosed with fibrosis.”

As described in a new paper published in Nature Biomedical Engineering, the UIC researchers engineered a thin microgel that, when designed in a specific way, can boost the therapeutic potential of MSCs to degrade scar tissue and regenerate healthy tissue in mouse models of fibrosis.

Shin and his colleagues engineered the microgel, which is as soft as healthy lung tissue, and incorporated a small protein called tumor necrosis factor-alpha. Also known as TNF-alpha, this protein acts as an inflammatory signal that encourages MSCs to synthesize collagenase. Collagenase is an enzyme that degrades excess collagen in fibrotic tissues and promotes the restoration of damaged tissues.

To optimize the MSCs with the microgel, the UIC researchers designed a microfluidic device to encapsulate individual cells rapidly and consistently in the thin gel.

“We miniaturized down to the small scale, the individual cell, which is important for delivery of the therapeutic into the tiny airways of the lungs,” said study first author Sing-Wan Wong, a UIC postdoctoral research associate in the department of pharmacology and regenerative medicine.

In models of fibrotic injury, the UIC researchers observed reduced indicators of scaring and increased indicators of healthy lung tissue, such as normal collagen levels and architecture, only among the mice treated with MSCs coated in their TNF-alpha-incorporated gel via single cell encapsulation.

“This is really one of the first scientific demonstrations that collagen levels can be normalized well after fibrotic injury, and that the cell environment, not just the cells themselves, can be designed at the single-cell level in a precise manner,” Shin said. “Our results suggest a feasible approach to predictively program cellular functions for desired therapeutic outcomes.”

Co-authors of the study are Chandra Tamatam, Ik Sung Cho, Peter Toth, Raymond Bargi, Patrick Belvitch, James Lee, Jalees Rehman and Sekhar Reddy.

This research was supported by grants from the National Institutes of Health (R01HL141255, R00HL125884, R01GM124235, R01HL136946).

Featured image: Gel-coated (red) mesenchymal stromal cells (yellow) can degrade collagen (green) over a distance in the presence of tumor necrosis factor-alpha. (Image: Jae-Won Shin/UIC)

Reference: Wong, S.W., Tamatam, C.R., Cho, I.S. et al. Inhibition of aberrant tissue remodelling by mesenchymal stromal cells singly coated with soft gels presenting defined chemomechanical cues. Nat Biomed Eng (2021). https://doi.org/10.1038/s41551-021-00740-x

Provided by UIC

Targeting Mechanosensitive Protein Could Treat Pulmonary Fibrosis (Medicine)

Researchers at the University of Alabama at Birmingham have identified a new molecular target that could potentially treat the deadly, aging-related lung disease idiopathic pulmonary fibrosis (IPF). The study, which will be published March 10 in the Journal of Experimental Medicine (JEM), suggests that targeting a protein called MDM4 could prevent respiratory failure by initiating a genetic program that removes scar tissue from the lungs.

IPF is characterized by the accumulation of scar tissue that stiffens the lungs and makes it difficult for patients to breathe and get sufficient oxygen into their blood. Though the causes of IPF remain unclear, age is a significant risk factor: the disease is estimated to affect 1 in 200 US adults over the age of 70.

The scars are thought to arise from a runaway wound healing process in which lung cells deposit excessive amounts of collagen into their surroundings, stiffening the lung tissue and activating highly contractile cells called myofibroblasts. These myofibroblasts produce still more collagen fibers and stiffen the tissue even further.

“Lung fibrosis resolution is thought to involve degradation of excessive collagen, removal of myofibroblasts, and regeneration of normal lung tissue by stem cells,” says Yong Zhou, an associate professor in the Department of Medicine, University of Alabama at Birmingham. “However, the mechanisms underlying the reversal of lung fibrosis remain poorly understood.”

Zhou and colleagues, including first author Jing Qu, discovered that the levels of a protein called MDM4 are elevated in the myofibroblasts of IPF patients and are also increased in aged mice with pulmonary fibrosis. The researchers found that the protein is produced in response to the increased stiffness associated with IPF.

MDM4 is known to inhibit a key transcription factor called p53. Zhou and colleagues found that reducing MDM4 levels activates a p53-dependent genetic program that makes myofibroblasts more likely to die and be removed from fibrotic tissues. Removing the Mdm4 gene from collagen-producing fibroblasts and myofibroblasts promoted the resolution of lung fibrosis in aged mice.

The researchers also found that treating mice with chebulic acid, a naturally occurring compound that removes the chemical cross-links between collagen fibers, could soften fibrotic tissue, increase enzyme-mediated collagen degradation, and reduce MDM4 levels, again resulting in the resolution of lung fibrosis.

“Targeting the mechanical properties of the lung microenvironment represents a promising strategy for anti-fibrotic therapy,” says Zhou. “Our study identifies MDM4 as a mechanosensitive protein and a novel molecular target in pulmonary fibrosis and highlights the therapeutic potential of targeting collagen cross-linking to reverse persistent lung fibrosis associated with aging.”

Featured image: Compared with a control (left), removal of the Mdm4 gene (right) favors the resolution of fibrotic scar tissue in the lungs of aged mice. ©2021 Qu et al. Originally published in Journal of Experimental Medicine. https://doi.org/10.1084/jem.20202033

Reference: Jing Qu, Shan-Zhong Yang, Yi Zhu, Ting Guo, Victor J. Thannickal, Yong Zhou; Targeting mechanosensitive MDM4 promotes lung fibrosis resolution in aged mice. J Exp Med 3 May 2021; 218 (5): e20202033. doi: https://doi.org/10.1084/jem.20202033 https://rupress.org/jem/article-lookup/doi/10.1084/jem.20202033?PR

Provided by Rockefeller University Press