Could humans grow new lungs?
A new finding about how lung tissue regenerates in mice could offer hope for millions of people living with respiratory disease such as COPD that occurs from environmental toxins and smoking.
Scientists have known mice can regenerate lung tissue. Now they’ve discovered biochemical signals that make that happen. The researchers believe the finding could be applied to humans.
In the new study, researchers at Weill Cornell Medical College say they have discovered how to “turn on” the signals needed to regenerate alveoli in the lungs – the small sacs at the bottom of the lungs where oxygen exchange takes place.
In their studies, the scientists found regeneration of lung tissue starts in endothelial cells that line the blood vessels in the lungs.
"It is speculated, but not proven, that humans have the potential to regenerate their lung alveoli until they can't anymore, due to smoking, cancer, or other extensive chronic damage," says Dr. Rafii, an investigator at the Howard Hughes Medical Institute.
"Our hope is to take these findings into the clinic and see if we can induce lung regeneration in patients who need it, such as those with chronic obstructive pulmonary disease (COPD)."
Dr. Ronald G. Crystal, who is a co-author of this study and professor of pulmonary and genetic medicine at Weill Cornell, said he envisions the day when patients with COPD could be treated using endothelial growth factors that come from lung blood vessels.
In their study, the scientists discovered molecular signals that regenerate liver and bone marrow that they call "angiocrine factors”. They found out the same factors can also regenerate lung tissue in mice, and possibly humans.
"Blood vessels are not just the inert plumbing that carries blood. They actively instruct organ regeneration," says Dr. Rafii. "This is a critical finding. Each organ uses different growth factors within its local vascular system to promote regeneration."
In mice, Rafi and colleagues found lungs regenerate in response to trauma. They removed the left lungs of mice then watched how the right lung regenerates to replace lost alveoli up to 80 percent.
Dr. Bi-Sen Ding, a postdoctoral fellow in Dr. Rafii's lab and the first author of this paper said, "This regeneration process also restores the physiological respiratory function of the lungs, which is mediated by amplification of various epithelial progenitor cells and regeneration of the alveolar sacs.”
Next, the researchers looked for the biochemical signal that starts regeneration of lung tissue.
They discovered the process starts with stimulation of receptors on lung endothelial cells that respond to vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2).
When VEGF and FGF2 are activated, a protein called matrix metalloproteinase-14 (MMP14) releases epidermal growth factors (EGF) that regenerates new lung tissue.
When the researchers took away VEGF and FGF-2 the remaining lung didn’t regenerate, but when the mice received an endothelial cell transplant from a normal mouse, the production of MMP14 was restored and functional alveoli regenerated.
"The recovery of lung function and lung mechanics by transplantation of endothelial cells that stimulate MMP14 production may be valuable for designing novel therapies for respiratory disorders," says Dr. Stefan Worgall, who helped with the functional lung studies in this project.
“This study will also help us understand mechanisms for repair in the growing lungs of infants and children," he adds.
Rafi explains MMP14 is the crucial "angiocrine" signal needed to regrow new lung tissue that can restore normal breathing when alveoli are absent or damaged.
"Changes in local blood flow and biomechanical forces in the remaining lung after removal of the left lung could certainly be one of the initiation cues that induce endothelial activation," says Dr. Sina Rabbany, co-senior author of the study.
Ding says there is no direct evidence that the same thing can happen in humans, but the researchers believe the same process occurs. It may be that alveoli become damaged to the point that they no longer produce signals to regenerate, especially in smokers with COPD.
Dr. Zev Rosenwaks, who is the director of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Weill Cornell, and a co-author of the study, said the researchers are generating pluripotent stem cells from patients with genetic lung disorders. The team hopes to find pathways that can help advance understanding of how endothelial cells can improve lung function.
The researchers believe it may be possible for humans to grow new lung tissue where oxygen exchange takes place now that they’ve discovered the molecular process in mice. If studies also find the same can happen in humans, it would lead to new and exciting treatments to help millions of people living with COPD for which there is currently no effective treatment.
"Endothelial-Derived Angiocrine Signals Induce and Sustain Regenerative Lung Alveolarization"
Bi-Sen Ding et al.
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