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Stem cells created to treat lung conditions...

A research project shows how to harvest lung stem cells noninvasively to create a powerful therapy against inflammatory lung diseases...


A team of scientists from the University of North Carolina (UNC) School of Medicine and North Carolina State University (NCSU) has developed promising research towards a possible stem cell treatment for several lung conditions — such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cystic fibrosis — often-fatal conditions that affect tens of millions of Americans.

In the journal (1) Respiratory Research, scientists demonstrate how they could harvest lung stem cells from people with a relatively non-invasive, doctor's-office technique — a bronchoscope inserted into the airways. They then able multiplied the harvested lung cells in the lab in order to yield enough cells sufficient for that patient's therapy.

In a second study, published in the journal (2) Stem Cells Translational Medicine, the team used the same collection technique and expansion of cells collected to successfully treat a model of Idiopathic Pulmonary Fibrosis or IPF - a chronic, irreversible, and ultimately fatal disease characterized by a progressive decline in lung function.

The researchers have been in discussions with the Food and Drug Administration (FDA) and are preparing an application for an initial clinical trial in patients with IPF.
"This is the first time anyone has generated potentially therapeutic lung stem cells from minimally invasive biopsy specimens."

Jason Lobo MD, Assistant Professor, Medicine, UNC and Medical Director, Lung Transplant and Interstitial Lung Disease, and co-senior author of both papers.

Co-senior author Ke Cheng, PhD, an associate professor in NCSU's Department of Molecular Biomedical Sciences and the UNC/NCSU Joint Department of Biomedical Engineering, said, "We think the properties of these cells make them potentially therapeutic for a wide range of lung fibrosis diseases."

These diseases of the lung involve the buildup of fibrous, scar-like tissue, typically due to chronic lung inflammation. As this fibrous tissue replaces working lung tissue, the lungs become less able to transfer oxygen to the blood. Patients ultimately are at risk of early death from respiratory failure. In the case of IPF, which has been linked to smoking, most patients live for fewer than five years after diagnosis.

The two FDA-approved drug treatments for IPF reduce symptoms but do not stop the underlying disease process. The only effective treatment is a lung transplant, which carries a high mortality risk and involves long-term use of immunosuppressive drugs.

Scientists have long studied the alternative of using stem cells to treat IPF and other lung fibrosis diseases. Stem cells are immature cells that can proliferate and become adult cells in order to repair injuries. Some types of stem cells have anti-inflammatory and anti-fibrosis properties that make them particularly attractive as potential treatments for fibrosis which is the formation of excess connective tissue in a reaction type process.

Cheng and Lobo focused on a set of stem cells and support cells that reside in the lungs and can be reliably cultured from biopsied lung tissue. The cells are called lung spheroid cells for the distinctive sphere-like structures they form when cultured. As the scientists reported in an initial paper in 2015, lung spheroid cells show powerful regenerative properties when used in a mouse model of lung fibrosis. In their mouse therapy trial, the cells outperformed other non-lung-derived stem cells known as mesenchymal stem cells, or multipotent connective tissue cells, that can differentiate into a variety of cell types. Mesenchymal stem cells are also under investigation to treat fibrosis.

In the first of the two new studies, Lobo and his team showed how they could obtain lung spheroid cells from human lung disease patients with a relatively non-invasive procedure called a transbronchial biopsy.
"We snip tiny, seed-sized samples of airway tissue using a bronchoscope. This method involves far less risk to the patient than does a standard, chest-penetrating surgical biopsy of lung tissue."

Jason Lobo MD

Cheng and his colleagues cultured lung spheroid cells from these tiny tissue samples until they were numerous enough - in the tens of millions - to be delivered therapeutically. When they infused the cells intravenously into mice, they found that most of the cells re-gathered in the animals' lungs. "These cells are from the lung, and so in a sense they're happiest, so to speak, living and working in the lung," Cheng mused.

In the second study, the researchers artificially induced a lung fibrosis condition in rats that closely resembled human IPF. They then injected the newly cultured spheroid cells into that group of rats. Upon studying these animals and another group treated with a placebo therapy, the researchers saw healthier overall lung cells and significantly less lung inflammation and fibrosis in the rats treated with lung spheroid cells.
"The treatment was safe and effective whether the lung spheroid cells were derived from the recipients' own lungs or from the lungs of an unrelated strain of rats. In other words, even if the donated stem cells were 'foreign,' they did not provoke a harmful immune reaction in the recipient animals, as transplanted tissue normally does."

Jason Lobo MD

Lobo and Chen expect that when used therapeutically in humans, lung spheroid cells initially would be derived from the patient to minimize any immune-rejection risk. Ultimately, however, to obtain enough cells for widespread clinical use, doctors might harvest them from healthy volunteers, as well as from whole lungs obtained from organ donation networks. The stem cells could later be used in patients as-is or matched immunologically to recipients in much the same way transplanted organs are typically matched.
"Our vision is that we will eventually set up a universal cell donor bank,"

Jason Lobo MD

Cheng, Lobo, and their teams are now planning an initial study of therapeutic lung spheroid cells in a small group of IPF patients and expect to apply later this year for FDA approval of the study. In the long run, the scientists hope their lung stem cell therapy will also help patients with other lung fibrosis conditions of which there are dozens, including COPD, cystic fibrosis, and fibro-cavernous pulmonary tuberculosis.

(1) Background Resident stem and progenitor cells have been identified in the lung over the last decade, but isolation and culture of these cells remains a challenge. Thus, although these lung stem and progenitor cells provide an ideal source for stem-cell based therapy, mesenchymal stem cells (MSCs) remain the most popular cell therapy product for the treatment of lung diseases. Surgical lung biopsies can be the tissue source but such procedures carry a high risk of mortality.

Methods
In this study we demonstrate that therapeutic lung cells, termed “lung spheroid cells” (LSCs) can be generated from minimally invasive transbronchial lung biopsies using a three-dimensional culture technique. The cells were then characterized by flow cytometry and immunohistochemistry. Angiogenic potential was tested by in-vitro HUVEC tube formation assay. In-vivo bio- distribution of LSCs was examined in athymic nude mice after intravenous delivery.

Results
From one lung biopsy, we are able to derive >50 million LSC cells at Passage 2. These cells were characterized by flow cytometry and immunohistochemistry and were shown to represent a mixture of lung stem cells and supporting cells. When introduced systemically into nude mice, LSCs were retained primarily in the lungs for up to 21 days.

Conclusion
Here, for the first time, we demonstrated that direct culture and expansion of human lung progenitor cells from pulmonary tissues, acquired through a minimally invasive biopsy, is possible and straightforward with a three-dimensional culture technique. These cells could be utilized in long-term expansion of lung progenitor cells and as part of the development of cell-based therapies for the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

Keywords:Pulmonary progenitor cells, Lung spheroid Stem cell

The lead authors of the two papers were Phuong-Uyen C. Dinh and Jhon Cores, both graduate research assistants in Cheng's laboratory.

The National Institutes of Health, the UNC General Assembly Research Opportunities Initiative, and the NC State Chancellor's Innovation Fund funded this research.


(2) Adult Lung Spheroid Cells Contain Progenitor Cells and Mediate Regeneration in Rodents With Bleomycin-Induced Pulmonary Fibrosis.

Abstract
Lung diseases are devastating conditions and ranked as one of the top five causes of mortality worldwide according to the World Health Organization. Stem cell therapy is a promising strategy for lung regeneration. Previous animal and clinical studies have focused on the use of mesenchymal stem cells (from other parts of the body) for lung regenerative therapies. We report a rapid and robust method to generate therapeutic resident lung progenitors from adult lung tissues. Outgrowth cells from healthy lung tissue explants are self-aggregated into three-dimensional lung spheroids in a suspension culture. Without antigenic sorting, the lung spheroids recapitulate the stem cell niche and contain a natural mixture of lung stem cells and supporting cells. In vitro, lung spheroid cells can be expanded to a large quantity and can form alveoli-like structures and acquire mature lung epithelial phenotypes. In severe combined immunodeficiency mice with bleomycin-induced pulmonary fibrosis, intravenous injection of human lung spheroid cells inhibited apoptosis, fibrosis, and infiltration but promoted angiogenesis. In a syngeneic rat model of pulmonary fibrosis, lung spheroid cells outperformed adipose-derived mesenchymal stem cells in reducing fibrotic thickening and infiltration. Previously, lung spheroid cells (the spheroid model) had only been used to study lung cancer cells. Our data suggest that lung spheroids and lung spheroid cells from healthy lung tissues are excellent sources of regenerative lung cells for therapeutic lung regeneration.

Significance:
The results from the present study will lead to future human clinical trials using lung stem cell therapies to treat various incurable lung diseases, including pulmonary fibrosis. The data presented here also provide fundamental knowledge regarding how injected stem cells mediate lung repair in pulmonary fibrosis. ©AlphaMed Press.

Keywords:
Adult lung stem cells; Mesenchymal stem cells; Pulmonary fibrosis; Spheroid cell culture

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Mouse lung spheroid cells show powerful regeneration properties
when applied to a mouse model of lung fibrosis. Image Credit:
University of North Carolina at Chapel Hill, and North Carolina State University



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