Lab-grown lung tissue could lead to new cancer, asthma treatments A look at how Michigan Engineers created a biomaterial scaffold to help researchers from the U-M Medical School grow mature human lung tissue.

In a breakthrough that could one day lead to new treatments for lung diseases like asthma and lung cancer, researchers have successfully coaxed stem cells—the body’s master cells—to grow into three-dimensional lung tissue. This could be useful in future cell-based therapies that repair damaged lungs by cultivating new, healthy tissue.

University of Michigan researchers grew the tissue by injecting stem cells into a specially developed biodegradable scaffold, then implanting the device in mice, where the cells grew and matured into lung tissue. The team’s findings were published in the Nov. 1 issue of the journal eLife.

Briana Dye, a PhD candidate in Cell & Developmental Biology at the University of Michigan Medical School, demonstrates the process of developing lung organoid tissue samples. This research was conducted partly in the lab of Lonnie Shea, the William and Valerie Hall Department Chair and Professor of Biomedical Engineering. Photo: Evan Dougherty, Michigan Engineering Communications & Marketing

Respiratory diseases account for nearly 1 in 5 deaths worldwide, and lung cancer survival rates remain low despite numerous therapeutic advances during the past 30 years. Cell-based therapies could be a key to improving treatment, helping damaged lungs heal in much the same way as a bone marrow transplant can treat leukemia. But the complexity of lung tissue makes such treatments much more difficult to develop.

“Lung tissue needs to be able to form into specific structures like airways and bronchi, and they all need to be able to work together inside the lung. So we can’t just add in healthy adult cells,” said Lonnie Shea, the William and Valerie Hall Department Chair of Biomedical Engineering and a professor of biomedical engineering at U-M. “Instead, we’re looking at delivering the precursors to these cells, then giving them the cues they need to develop and mature on their own. This project was a step in that direction.”

While previous experiments had successfully grown lung cells, the cells were immature and disorganized. So Shea worked with a U-M medical school team led by Briana Dye, a graduate student in the U-M Department of Cell and Developmental Biology, on a new approach. They developed a three-dimensional, biodegradable scaffold that helped the lung cells mature and begin to develop into structures like those inside an actual lung.

Made of PLG, a spongy, biodegradable material, the scaffold was shaped like a small cylinder approximately five millimeters wide and two millimeters tall. The team injected stem cells into the scaffold, transplanted it into mice, then allowed the cells to mature for eight weeks.

The scaffold provided a stiff structure that supported growth of the mini lungs after transplantation while still allowing the transplanted tissue to become vascularized, growing blood vessels that supplied it with nutrients.

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When the team examined the tissue, they found that it had not only survived, it had developed tube-shaped airway structures similar to the airways in adult lungs. It also developed mucus-producing cells, multiciliated cells and stem cells similar to those found in adult lungs.

“In many ways, the tissue grown in the study was indistinguishable from human adult tissue,” says senior study author Jason Spence, Ph.D., associate professor in the U-M Department of Internal Medicine and the Department of Cell and Developmental Biology at the U-M Medical School.

The researchers caution that they’re far from growing anything like a complete human lung—the tissue grown in the experiment was a mass of lung cells scattered among other types of cells inside the scaffold. But they say it’s an important early step that can yield valuable information about how healthy cells grow and develop. In the future, that could lead to new treatments for lung disease.

Richard Youngblood, a second year PhD student in Biomedical Engineering at the University of Michigan, demonstrates the construction of a lung organoid PLG scaffold. This research was conducted partly in the lab of Lonnie Shea, the William and Valerie Hall Department Chair and Professor of Biomedical Engineering. Photo: Evan Dougherty, Michigan Engineering Communications & Marketing

“What if we could regrow a portion of a damaged lung, like a patch?” Shea said. “Treatments like that, while challenging, may be possible.”

The lung tissue is one of several types of cultured organ tissue, or “organoids” that U-M research teams have developed—other cell types they’ve created include intestines, pancreatic cells and placenta cells. In addition to their uses in developing new cell-based therapy, Shea says the cells can provide a human model for screening drugs, studying gene function, generating transplantable tissue and studying complex human diseases like asthma.

“Organoids enable us to see the development and formation of an organ without having to conduct a test on an entire organism. And once we understand that, we can find new ways of repairing organs that are injured, or that haven’t developed properly.”

The paper is titled “A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids.” The research was supported by the National Institutes of Health (grant number R01 HL119215), by the NIH Cellular and Molecular Biology training grant at Michigan and by the U-M Tissue Engineering and Regeneration Training Grant.

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U-M Schools and Colleges Form Regenerative Medicine Collaborative

March 31, 2017

ANN ARBOR, MI –A Regenerative Medicine Collaborative, formed with support from U-M Office of Research, College of Engineering, and School of Medicine, aims to foster connections and enable new initiatives among investigators at the major U-M schools and colleges, including: U-M Engineering, Medical School, Dentistry, LSA, Public Health, and Pharmacy.

The University of Michigan Office of Research charged a planning task force to evaluate The University of Michigan’s strength in regenerative medicine. U-M ranks #5 in the world for regenerative medicine related citations and the stakeholder group has received nearly $320 million from NIH over the last five years for related research. We are among the leaders in the number of patents awarded, with faculty interested in regenerative and restorative medicine submitting over 320 invention disclosures resulting in greater than 120 patent filings in the past five years.

A web site (http://regenerativemedicine.umich.edu) and monthly highlights aim to communicate the breadth and depth of regenerative medicine work being done at U-M. Furthermore, the regenerative medicine collaborative will solicit a call for themes to identify areas in which U-M can grow or lead an area. The initiative will, also, facilitate the assembly of teams to be competitive for large-scale initiatives and projects across disciplines.

In addition to the website and monthly highlights, a launch symposium is being planned for the summer of 2017 to welcome the stakeholders. If you are interested in receiving the newsletters or attending the symposium, please send an email request to Amalia DiRita (amdirita@umich.edu).


Nanoparticle Acts Like Trojan Horse To Halt Asthma

Ann Arbor – In an entirely new approach to treating asthma and allergies, a biodegradable nanoparticle acts like a Trojan horse, hiding an allergen in a friendly shell to convince the immune system not to attack it, according to new research from the University of Michigan and Northwestern University. As a result, the allergic reaction in the airways is shut down long term and an asthma attack prevented.

The technology can be applied to food allergies as well. The nanoparticle is currently being tested in a mouse model of peanut allergy, similar to food allergy in humans.

“Small quantities of allergen have been used to de-sensitize patients, and that delivering the allergen using emerging nanotechnologies can provide a more efficient and effective system” said senior author Lonnie Shea, the William and Valerie Hall Chair and Professor of Biomedical Engineering at the University of Michigan and adjunct professor at Northwestern.

The treatment can be applied to any allergy simply by loading the nanoparticle with the target allergen – from ragweed pollen to peanut protein.

In addition, the treatment makes use of an already FDA-approved material; the nanoparticles are composed of PLGA, a biopolymer that includes lactic acid and glycolic acid.

When the loaded nanoparticle is injected into the bloodstream of mice, the immune system sees the particle as innocuous debris. Then the nanoparticle and its hidden cargo are consumed by a macrophage, essentially a vacuum-cleaner cell.

“The vacuum-cleaner cell presents the allergen to the immune system in a way that says, ‘No worries, this belongs here,’” said Stephen Miller, another senior author on the study and the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. The immune system then shuts down its attack on the allergen, and the immune system is reset to normal.

The allergen, in this case egg protein, was administered into the lungs of mice who had been pretreated to be allergic to the protein and already had antibodies in their blood against it. After being treated with the nanoparticle, however, they no longer had an allergic response to the allergen.

The approach creates a more normal, balanced immune system by increasing the number of regulatory T cells – immune cells important for recognizing the airway allergens as normal – while turning off the allergy-causing Th2 T cells.

It’s the first time this method for creating tolerance in the immune system has been used in allergic diseases. The approach has been used in autoimmune diseases including multiple sclerosis and celiac disease in previous preclinical research at Northwestern, and a clinical trial using the nanoparticles to treat celiac disease is in development.

“The findings represent a novel, safe and effective long-term way to treat and potentially ‘cure’ patients with life-threatening respiratory and food allergies,” said Miller.

The asthma allergy study was in mice, but the technology is progressing to clinical trials in autoimmune disease. The nanoparticle technology is being developed commercially by Cour Pharmaceuticals Development Co. A clinical trial using the nanoparticles to treat celiac disease is in development.

More information: Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization, PNAS, www.pnas.org/cgi/doi/10.1073/pnas.1505782113

Read more at: http://phys.org/news/2016-04-nanoparticle-trojan-horse-halt-asthma.html#jCp

The research was supported in part by grant EB-013198 from the National Institute of Biomedical Imaging and Bioengineering and grant NS-026543 from the National Institute of Neurological Disease and Stroke, both of the National Institutes of Health (NIH), the Dunard Fund and a predoctoral fellowship TL1R000108 from the NIH National Center for Research Resources and the National Center for Advancing Translational Sciences.


Researchers use ovarian follicles to preserve fertility Technique could be beneficial for women with cancer; study in mice produced live births

From: U-M Comprehensive Cancer Center News
Media contact: Nicole Fawcett, 734-764-2220 |  Patients may contact Cancer AnswerLine™, 800-865-1125

ANN ARBOR, Mich. — Researchers at the University of Michigan have identified a potential new approach to fertility preservation for young cancer patients that addresses concerns about beginning cancer treatment immediately and the possibility of reintroducing cancer cells during the fertility preservation process.

The work, done in mice, has potential to expand options for girls and women undergoing cancer treatments that may impact their future fertility.

The researchers isolated primary ovarian follicles, consisting of the oocyte and surrounding cells. They encapsulated the follicles in a gel and then reimplanted them in mice. All mice transplanted with the follicles resumed normal ovarian cycles. One-third produced live births.

For many young women diagnosed with cancer, concerns about fertility rank high and may influence their decisions about cancer treatment. Current fertility preservation options for women include embryo or egg freezing, performed using hormonal stimulation to induce ovulation. Hormonal stimulation is not possible for all young patients. Some are too young and some cannot afford to delay cancer treatment.

Jacqueline Jeruss“This research is an important advance in the potential expansion of fertility preservation options for young patients who may not be able to undergo hormone stimulation to induce ovulation before beginning chemotherapy,” says study author Jacqueline S. Jeruss, M.D., Ph.D., associate professor of surgery and director of the Breast Care Center at the University of Michigan Comprehensive Cancer Center.

“This study also provides new information on a method to reduce or eliminate cancer cell exposure during the fertility preservation process,” she adds.

Fear of reintroducing cancer

Researchers are also studying ovarian tissue transplantation for patients with cancer. A key concern with this approach is the risk that the ovarian tissue may harbor latent cancer cells that, upon transplantation, could be reintroduced back into the patient. Cancer cells are known to circulate throughout the body even in early stage invasive disease.

In this new study, when researchers isolated the follicles, they substantially reduced the presence of cancer cells. Two of the five tested transplanted materials had no residual cancer cells.

Lonnie Shea“The success rate for traditional in vitro fertilization is approximately 33 percent per cycle. For cancer patients, the oocytes or embryos that are cryo-preserved before cancer treatment may become their entire reproductive future,” says study author Lonnie D. Shea, Ph.D., William and Valerie Hall Chair and professor of biomedical engineering at the University of Michigan.

“The ovary can have tens to hundreds of thousands of follicles. If we can access that pool to preserve fertility, we could potentially create many more chances for reproductive success for these patients,” Shea adds.

Refining the technique

The authors tested three types of biomaterial for preserving the follicles. They hope that by refining their study techniques they can produce even better results. Additional research is also needed to ensure that all cancer cells are consistently eliminated from the follicles every time this tissue is transplanted.

As the work’s promise continues, the researchers envision that ovarian follicles could be extracted and preserved till the woman was ready to pursue pregnancy. At that point, the follicles would be matured and then fertilized. More research is needed before this technique can be tested in humans.

“Fertility is an important part of survivorship for young cancer patients,” Jeruss says. “It’s crucial to identify new techniques to make more fertility preservation options available for women and girls being treated for cancer.”

The study is published in the Nature journal Scientific Reports.

Note to patients: This work was done in mice and is not currently available for use in humans. Call the Cancer AnswerLine at 800-865-1125 to speak to a nurse about available fertility preservation options.

Additional authors: Ekaterina Kniazeva and Teresa K. Woodruff, from Northwestern University; A.N. Hardy from Fox Chase Cancer Center; Samir Boukaidi, from Centre Hospitalier Universitaire de Nice

Funding: National Institutes of Health grant U54 HD076188

Disclosure: None

Reference: Scientific Reports, “Primordial Follicle Transplantation within Designer Biomaterial Grafts Produce Live Births in a Mouse Infertility Model,” published online Dec. 3, 2015,doi:10.1038/srep17709