Study Gives First Evidence That Adult Human Lungs Can Regrow

Researchers speculate growth was stimulated, at least in part, by stretching caused by exercise

By Barbara Bronson Gray
HealthDay Reporter

WEDNESDAY, July 18 (HealthDay News) -- Researchers have uncovered the first evidence that the adult human lung is capable of growing back -- at least in part -- after being surgically removed.
In an observational study, researchers used MRIs with hyperpolarized helium-3 gas to show that existing alveoli -- the tiny, air-exchange units of the lung -- actually increased in number after a 33-year-old woman had her entire right lung removed due to cancer.

The study showed a 64 percent increase in the number of alveoli in the woman's lung 15 years after surgery. "The research clearly shows that some form of lung growth can occur in the adult human," said study author James Butler, an associate professor of medicine in the department of medicine at Harvard Medical School in Boston.

The new alveoli were all shaped similarly. "It's striking, the degree of homogeneity of the new alveoli, as if the lung was responding to something," Butler added. The cause of the new growth could be stretching of the tissue, perhaps by exercise, he suggested. "Could other bio-molecular growth be triggered by stretch? It's a wide-open question now."

About a year and a half after surgery, the woman began a daily exercise program including walking, cycling and yoga. Previous studies in adult dogs have suggested that lung growth after pneumonectomy (removal of the lung) in dogs was possible, typically after periods of lung stress or strain.
Over a period of 15 years, data measuring lung size and capacity were collected, using common respiratory tests (called FEV and FVC) measuring how much air can be taken in and blown out with deep breaths. In the early months after surgery, the lung responded as researchers would expect. The total lung volume increased and the lung density fell below normal. But, the lung tissue volume gradually started to increase and the density returned to a level normally seen when a deep breath is taken, suggesting the growth of new tissue.


The ability of the lung to regenerate, potentially triggered by exercise, makes sense, said Dr. Norman Edelman, a professor of medicine at Stony Brook University and chief medical officer of the American Lung Association. "When the lung develops in utero [when the fetus is developing], the pulling force of the diaphragm is an important stimulation for the lung to grow," he said. "But, of course, the practical application of the research is a long way off."
Butler said the next step is to do a study involving more people over time. "If we can discover the underlying bio-molecular mechanisms, they would suggest potential therapeutic options," he explained.

 see the original article here

Lung Regeneration Closer to Reality after New Discovery

Researchers from Weill Cornell Medical College say they have taken an important step forward in their quest to "turn on" lung regeneration - a discovery that could lead to treatment for millions of people suffering from respiratory disorders.

In the journal Cell, the research team claims that they have discovered the biochemical signals in mice that initiate the regeneration of new lung alveoli: the tiny, numerous sacs within the lung where oxygen exchange occurs. Specifically, they found that regenerative signals originate from the specialized endothelial cells that line the interior of blood vessels in the lung.

Though it has been long known that mice can regenerate and expand the capacity of one lung if the other is missing, this study now pinpoints the molecular triggers that initiate this process, and the researchers believe these findings hold relevance for humans.

According to lead author, Dr. Shahin Rafii, "Several adult human organs have the potential upon injury to regenerate to a degree, and while we can readily monitor the pathways involved in the regeneration of liver and bone marrow, it is much more cumbersome to study the regeneration of other adult organs, such as the lung and heart.”

For the study, Dr. Bi-Sen Ding, first author of this paper, removed the left lungs of mice and studied the biochemical process of subsequent regeneration of the remaining right lung. Prior research has shown that when the left lung of mice is removed, the right lung regenerates by 80 percent, effectively replacing most of the lost alveoli.

htclick for the complete article on lungs




The researchers found that removal of the left lung triggers receptors on lung endothelial cells that respond to vascular endothelial growth factor and basic fibroblast growth factor. Activating these receptors promotes the creation of another protein known as MMP14. The researchers discovered that MMP14, by releasing epidermal growth factors, sparks the generation of new lung tissue.

The next step for researchers will be to determine in MMP14 and other unrecognized angiocrine factors are responsible for lung regeneration in humans as well as mice. According to Dr. Ding, "We believe the same process goes on in humans, although we have no direct evidence yet.” The study’s authors theorize that patients with COPD have so much damage to their lung endothelial cells that they no longer produce the proper inductive signals, thus impairing lung regeneration.

Co-author of the study, Dr. Zev Rosenwaks theorizes that, “"Perhaps replacement of angiocrine factors, or transplantation of normal lung endothelial cells derived from pluripotent stem cells, could restore lung regeneration. Currently, we are generating pluripotent stem cells derived from patients with genetic pulmonary disorders to identify potential pathways, which may ultimately enhance our understanding of how lung endothelial cells may improve lung function in these patients."

stem cells to reverse Effects of Emphysema

Transplantation of Autologous Stem Cells Found to Reverse Effects of Emphysema

A novel stem cell therapy could be a viable treatment for patients with emphysema.   Previous methods to treat advanced lung disease involved transplanting stem cells intravenously.  In this new study, researchers used an endoscopic delivery system coupled with a scaffold comprised of natural extracellular matrix components to transplant autologous lung-derived mesenchymal stem cells (LMSCs) into the lungs of [animal] subjects with emphysema.  Post-transplantation results indicated marked evidence of tissue regeneration, increased blood flow to the lungs, and increased extra cellular matrix content.

 ”Mensenchymal stem cells are considered for transplantation because they are readily available, highly proliferative and display multi-lineage potential,” said study corresponding author Dr. Edward P. Ingenito of the Brigham and Women’s Hospital Division of Pulmonary and Critical Care Medicine.
The study is indicative of the multidisciplinary approach to the usage of autologous stem cells opening the door to a multitude of new possibilities for innovative stem cell therapies in a biologically organic way: using the body’s own regenerative properties to heal itself through the unique power of stem cells.


Preserving one’s own mesenchymal stem cells provides biological insurance for families and assurance that they will have access to progressive therapies when they need them most.  Banking the highly proliferative mesenchymal stem cells found in the dental pulp of baby teeth and wisdom teeth is an easy and affordable way to insure the future health of your family.
To learn more about how to bank dental stem cells, visit www.stemsave.com or call 877-783-6728 (877-StemSave) today.
To view the full article, click here.
The future of Regenerative Medicine is now.

Ancillary Studies of Lung Stem/Progenitor Cell Epithelial-Mesenchymal Signaling

Ancillary Studies of Lung Stem/Progenitor Cell Epithelial-Mesenchymal Signaling Abstract: Epithelial-mesenchymal signaling is essential for organogenesis and adult tissue maintenance but is poorly understood in lung repair and regeneration. This proposal exploits timely advances by Consortium investigators and the additional skills and resources of collaborating scientists to identify the critical mesenchymal and epithelial stem/progenitor cell populations that mediate lung regeneration and identify the key signaling factors that operate in lung bronchi, bronchioles, and alveoli. Sorted epithelial and mesenchymal cell populations will be scrutinized for evidence of signaling cascade activation separately in both epithelium and mesenchyme. Using murine genetic models and co-cultures of epithelial and mesenchymal cells, prioritized pathways, initially Sonic hedgehog (Shh), will be modulated to establish the role of pathway activation or dysfunction in airway homeostasis and during regeneration. Parallel in vitro models for primary human lung cells will be developed. Additionally, normal and pathologic pathway activation will be assessed in human lung tissue by in situ hybridization and immunohistochemistry. The Aims are: 1) To lineage trace and sort region-specific epithelial progenitor cells and mesenchyme to identify candidate signaling pathways mediating epithelial-mesenchymal crosstalk; 2) To define the role of Shh signaling in epithelial and niche interactions in airway homeostasis and after lung injury; and 3) To employ novel human lung cell in vitro coculture models to test the function of candidate epithelial-mesenchymal signaling pathways identified in mice and to examine expression of cognate molecules in normal and diseased human lung tissues. These studies will exploit the skills, knowledge and tools of the Progenitor Cell Biology Consortium and this Ancillary team and will leverage these assets to enhance our understanding of lung regenerative biology. The information gained will be invaluable for defining mechanisms of normal lung repair and pathologic lung disease development, which lag behind our understanding in cardiac and bone marrow biology and disease. click for more info on lungs repair and regeneration

Trigger Discovered Inside Blood Vessels of the Lung for lung regeneration

Trigger Discovered Inside Blood Vessels of the Lung for lung regeneration



A molecular trigger involved in lung regeneration has been uncovered. Investigators--including Dr. Ronald G. Crystal (Chief of Pulmonary and Critical Care Medicine) and Dr. Shahin Rafii (Professor of Medicine/Medicine & Genetics)-- have published their findings in Cell. The discovery is part of a labyrinth of advances toward a fuller understanding of the process of lung regeneration.

Lead investigator, Dr. Rafii (Arthur B. Belfer Professor of Genetic Medicine & Co-Director of WCMC’s Ansary Stem Cell Institute), explains that the pathways involved in the regeneration of liver and of bone marrow can be monitored readily, but it is “much more cumbersome” to study the process in adult organs such as the lung or heart. Using a mouse model, the investigators uncovered growth factor signals that trigger – or “turn on”-the generation of new lung alveoli. Lung alveoli are the numerous, tiny sacs within the lung where oxygen exchange takes place during inhalation and exhalation. The regeneration process the researchers have defined in the journal Cell involves specialized cells (known as endothelial cells), which line the interior of blood vessels in the lung: These endothelial cells--by producing specific growth factors know as angiocrine factors--trigger and sustain the generation of new lung alveoli.

It has been long-known that when a mouse is missing one of its lungs, the remaining lung has the capacity to expand and regenerate. It is speculated that humans may have the same potential, unless, or until, prevented by smoking, cancer, or other extensive chronic damage. Dr. Crystal, co-author of the study, notes there is no effective therapy for patients with COPD. “Based on this study,” he says, “I envision a day when patients with COPD and other chronic lung disease may benefit from treatment with factors derived from lung blood vessels that induce lung regeneration.”


see the news release on on lung regeneration at Cornell University

Stem cells used for Lungs

Stem cells that are able to regenerate damaged lung tissue have been discovered by scientists. The brochioalveolar stem cells (BASCs), naturally present in the lungs of rodents and humans, are capable of rebuilding alveoli - the small air sacs in lungs.
Professor Frank McKeon, from the Genome Institute in Singapore and Harvard Medical School, hopes that the discovery of the stem cells will lead to new treatments for people with damaged lungs. 'We have found that the lungs do in fact have a robust potential for regeneration, and we've identified the specific stem cells responsible', he said.


The stem cells were isolated after researchers infected mice with a form of the H1N1 influenza virus - similar to the virus that caused the 1918 flu pandemic - to observe lung damage and regeneration. The virus initially damaged more than half of the lung alveolar tissue, but the alveoli had regenerated by three months after infection. There was no sign of lung fibrosis, a chronic scarring condition commonly seen after other forms of lung damage.

'We saw essentially pristine lungs at three months after a loss of 50 percent of lung tissue', said Professor McKeon, who led the team.
The cells multiply rapidly, migrate towards areas of damage in the lungs and assemble into 'pods' that go on to form new alveoli. Similar stem cells with the ability to multiply and form pod-like structures were also isolated in human lung tissue.
Researchers are now working to identify the signalling molecules and growth factors that promote lung regeneration at repair sites. Such work could result in improved therapies for acute and chronic lung damage caused by conditions such as asthma, chronic obstructive pulmonary disease and pulmonary fibrosis.

'These findings suggest new cell- and factor-based strategies for enhancing lung regeneration following acute damage from infection, and even in chronic conditions such as pulmonary fibrosis', said Professor McKeon. 'It's too early to say common lung diseases will be treatable, but it's a start, and there's a lot of potential'.
In another study, also published in the journal Cell, researchers at the Howard Hughes Medical Institute and Weill Cornell Medical College identified a key signalling molecule involved in regenerating alveoli and lung tissue.

The molecule - matrix metalloproteinase 14 (MMP14) - is required for the growth of new alveoli. When one lung is removed, new alveoli are known to grow in the other intact lung. But when the researchers blocked the activity of MMP14, the lung's regenerative capacity was impaired. Reintroducing MMP14 restored regeneration. The researchers found that cells in the blood vessels of the lungs produced MMP14.
'The key is that the blood vessels turn on the pathways for regeneration', said Dr Shahin Rafii, who led the research; 'the therapeutic potential is tremendous'.

SOURCES & REFERENCES

Distal Airway Stem Cells Yield Alveoli In Vitro and during Lung Regeneration following H1N1 Influenza Infection

Cell | 28 October 2011

Lung stem cells offer therapeutic clues

EurekAlert! | 27 October 2011

Regenerated Lungs from Stem Cells Bring Possible Therapy

International Business Times | 27 October 2011

Stem Cells that Rebuild Alveoli After Acute Respiratory Distress Syndrome Identified

Genetic Engineering & Biotechnology News | 28 October 2011

Stem-cell find breathes new life into lung repair

New Scientist | 28 October 2011 see complete article om stem cells and growing new lungs

A Breath of Fresh Air in Lung Regeneration

Referred to by: A Breath of Fresh Air in Lung Regeneration

 

• Highlights
• Pulmonary capillary endothelial cells (PCECs) support alveologenesis
• Autocrine VEGFR2 and FGFR1 activation in PCECs induces MMP14 expression
• MMP14 unmasks EGF receptor ligands, enhancing epithelial cell proliferation
• Injection of activated PCECs or angiocrine factors accelerates lung regeneration

Summary

To identify pathways involved in adult lung regeneration, we employ a unilateral pneumonectomy (PNX) model that promotes regenerative alveolarization in the remaining intact lung. We show that PNX stimulates pulmonary capillary endothelial cells (PCECs) to produce angiocrine growth factors that induce proliferation of epithelial progenitor cells supporting alveologenesis. Endothelial cells trigger expansion of cocultured epithelial cells, forming three-dimensional angiospheres reminiscent of alveolar-capillary sacs. After PNX, endothelial-specific inducible genetic ablation of Vegfr2 and Fgfr1 in mice inhibits production of MMP14, impairing alveolarization. MMP14 promotes expansion of epithelial progenitor cells by unmasking cryptic EGF-like ectodomains that activate the EGF receptor (EGFR). Consistent with this, neutralization of MMP14 impairs EGFR-mediated alveolar regeneration, whereas administration of EGF or intravascular transplantation of MMP14⁺ PCECs into pneumonectomized Vegfr2/Fgfr1-deficient mice restores alveologenesis and lung inspiratory volume and compliance function. VEGFR2 and FGFR1 activation in PCECs therefore increases MMP14-dependent bioavailability of EGFR ligands to initiate and sustain alveologenesis.

 

Authors

Bi-Sen Ding, Daniel J. Nolan, Peipei Guo, Alexander O. Babazadeh, Zhongwei Cao, Zev Rosenwaks, Ronald G. Crystal, Michael Simons, Thomas N. Sato, Stefan Worgall, Koji Shido, Sina Y. Rabbany, Shahin RafiiSee Affiliations

 

Howard Hughes Medical Institute, Ansary Stem Cell Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, New York, NY 10065, USA Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT 06510, USA Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan Bioengineering Program, Hofstra University, Hempstead, NY 11549, USA Corresponding author

 

trigger generation of new lung alveoli

 trigger generation of new lung alveoli



In the Oct. 28 issue of the journal Cell, the research team reports that they have uncovered the biochemical signals in mice that trigger generation of new lung alveoli, the numerous, tiny, grape-like sacs within the lung where oxygen exchange takes place. Specifically, the regenerative signals originate from the specialized endothelial cells that line the interior of blood vessels in the lung.

While it has long been known that mice can regenerate and expand the capacity of one lung if the other is missing, this study now identifies molecular triggers behind this process, and the researchers believe these findings are relevant to humans.

"Several adult human organs have the potential upon injury to regenerate to a degree, and while we can readily monitor the pathways involved in the regeneration of liver and bone marrow, it is much more cumbersome to study the regeneration of other adult organs, such as the lung and heart," says the study's lead investigator, Dr. Shahin Rafii, who is the Arthur B. Belfer Professor of Genetic Medicine and co-director of the Ansary Stem Cell Institute at Weill Cornell Medical College.

"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, who is also 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)."

"There is no effective therapy for patients diagnosed with COPD. Based on this study, I envision a day when patients with COPD and other chronic lung diseases may benefit from treatment with factors derived from lung blood vessels that induce lung regeneration," states Dr. Ronald G. Crystal, who is a co-author of this study and professor of pulmonary and genetic medicine at Weill Cornell.