Lung Stem Cells Heal Lungs and Point to Possible New Treatments

Frank McKeon, Ph.D., and Wa Xian, Ph.D. from Jackson Laboratory and their colleagues have identified the a certain lung stem cell, and the role it plays in regenerating lungs.

This work, which appeared in the Nov. 12 issue of the journal Nature, provides some much-needed clarification of the nuts and bolts of lung regeneration and provides a way forward for possible therapeutic strategies that harness these lung stem cells.

“The idea that the lung can regenerate has been slow to take hold in the biomedical research community,” McKeon says, “in part because of the steady decline that is seen in patients with severe lung diseases like chronic obstructive pulmonary disease (known as COPD) and pulmonary fibrosis.”

McKeon noted that there is ample evidence of a robust system for lung regeneration. “Some survivors of acute respiratory distress syndrome, or ARDS, for example, are able to recover near-normal lung function following significant destruction of lung tissue.”

This is a capacity that humans share with mice. Mice infected with the H1N1 influenza virus show progressive inflammation in the lung followed by the death and loss of important lung cell types. However, over the course of several weeks, the lungs of these mice recover and show no signs of previous lung injury.

Because of the presence of such robust lung regeneration in mice, these organisms provide a fine model system to study lung regeneration.

McKeon and his colleagues had previously identified a type of adult lung stem cell known as p63+/Krt5+ in the distal airways. When grown in culture, these p63+/Krt5+ lung stem cells neatly formed alveolar-like structures that were similar to those found within the lung. Alveoli are the tiny, specialized air sacs that form at the ends of the smallest airways, where gas exchange occurs in the lung. Following infection with H1N1, these same stem cells migrated to sites of inflammation in the lung and clustered together to form pod-like structures that resemble alveoli, both visually and molecularly.

McKeon and his colleagues reported that when the lung is damaged by H1N1 infraction, p63+/Krt5+ lung stem cells proliferate and contribute to the development of new alveoli near sites of lung inflammation.

To determine if these cells are required for lung regeneration, McKeon and his coworkers developed a novel system that utilizes genetic tools to selectively remove these cells from the mouse lung. Mice that lack p63+/Krt5+ lung stem cells cannot recover normally from H1N1 infection, and instead exhibit scarring of the lung and impaired oxygen exchange. This demonstrates the key role p63+/Krt5+ lung stem cells play in regenerating lung tissue.

To carry this work one step further, McKeon and his team isolated and subsequently transplanted p63+/Krt5+ lung stem cells into a damaged lung. The transplanted p63+/Krt5+ cells readily contribute to the formation of new alveoli, which nicely illustrates the capacity of these cells to regenerate damaged lung tissue.

In the U.S. about 200,000 people have Acute Respiratory Distress Syndrome, a disease with a death rate of 40 percent, and there are 12 million patients with COPD. “These patients have few therapeutic options today,” Xian says. “We hope that our research could lead to new ways to help them.”

Bone Progenitor Cells Discovered – Might Help Children Who Need Corective Facial Surgery

In children, bone grow thicker and longer and get stronger and denser. When children reach adolescence, they know that the time has come to stop growing longer and stronger. However, even into adulthood, bones still retain the capacity to heal. Why the differences between adolescents and adults? This is a question that has long fed the imaginations of scientists.

Recently, a collaborative team of biomedical researchers from the University of Michigan, Kyoto University and Harvard University has made the answer to this question a little clearer.

Dr. Noriaki Ono, U-M assistant professor of dentistry, and his collaborators discovered that a certain subset of cartilage-making cells – cells known as chondrocytes – proliferate and differentiate into other bone cells that drive bone growth. These discoveries could lead to new treatments for children with facial deformities who normally have to wait until adulthood for corrective surgery. This study appeared in the journal Nature Cell Biology.

A long-held view is that bone-making chondrocytes die once children reach adolescence and their bones stop growing. However, in adults, bone still heal without the benefit of these bone-making chondrocytes. How does this occur? This question has generated a fair amount of disagreement between researchers.

Ono’s group discovered that some of these bone-making chondrocytes don’t die. Instead, they are transformed into other types of bone-growing and bone-healing cells.

“Up until now, the cells that drive this bone growth have not been understood very well. As an orthodontist myself, I have special interest in this aspect, especially for finding a cure for severe bone deformities of the face in children,” he said. “If we can find a way to make bones that continue to grow along with the child, maybe we would be able to put these pieces of growing bones back into children and make their faces look much better than they do.”

According to Ono, one of the challenges in bone and cartilage medicine is that resident stem cells haven’t really been identified. The only widely accepted idea is that certain stem cells like mesenchymal stem cells help bones heal and other help them grow, but the progenitor cells for these cell populations and what goes wrong with them in conditions such as osteoporosis remains mysterious.

Ono and his team used a technique called “fate mapping,” which labels cells genetically and them follows them throughout development. Ono and others came upon a specific precursor cell that gives rise to fetal chondrocytes, and all the other later bone-making cells and . By mesenchymal stromal cells later in life. Most exciting, Ono and his coworkers found a way to identify the cells responsible for growing bone. By identifying these cells, isolating them and even implanting them into the skull or long bones of a child with a bone deformity condition, the cells would make bone that would also grow with the child.

Many factors cause craniofacial deformities. These types of deformities can place pressure on the brain, eyes, or other structures and prevent them from developing normally. For example, children with Goldenhar syndrome have underdeveloped facial tissues that can harm the developing jawbone. Another bone deformity called deformational plagiocephaly causes a child’s head to grow asymmetrically. Maybe the implantation of such cells can provide a way to restart the abnormally growing bones in these children.