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.

Animated GIF - Find & Share on GIPHY

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.

Credits:


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).


U-M leads major new regenerative medicine center funded by NIH

ANN ARBOR—A new interdisciplinary health sciences resource center at the University of Michigan has received an $11.7 million award from the National Institutes of Health to advance regenerative medicine.

The center, led by the School of Dentistry, brings together scientists, engineers and clinicians from several U-M departments in collaboration with researchers at the University of Pittsburgh, Harvard University and private companies.

They will investigate new ways to restore dental, oral and craniofacial tissues lost to disease, injury or congenital disorders. Technologies advanced in these areas could lead to tissue engineering applications for other parts of the body as well.

The research, funded by the National Institute of Dental and Craniofacial Research, involves U-M collaborators from the Medical School, School of Public Health, College of Pharmacy, College of Engineering, Office of Technology Transfer and Michigan Institute for Clinical and Health Research. Other co-investigators are from the McGowan Institute at Pittsburgh and the Wyss Institute for Biologically Inspired Engineering at Harvard.

The center is named the Michigan-Pittsburgh-Wyss Resource Center: Supporting Regenerative Medicine in Dental, Oral and Craniofacial Technologies. The three universities have committed financial support in addition to the $11.7 million NIH award to create a project total of about $14 million.

The U-M-based resource center is one of two announced today by the NIDCR. The other is based at the University of California, San Francisco. The combined NIH awards total $24 million over three years.

The collaboration of the Michigan, Pittsburgh and Harvard researchers came out of an initial one-year organizational phase funded with a previous NIDCR planning grant. The new funding supports a second, three-year phase during which investigators will evaluate and select research projects that have the most scientifically sound, clinically applicable and commercially viable strategies for the regeneration of dental, oral and craniofacial tissues.

The resource center will match the projects with engineering, biological, manufacturing, commercial and regulatory expertise from the clinical, academic and private sectors in order to more efficiently translate discoveries into clinical practice.

Regenerative medicine refers to research that integrates engineering and biology, seeking to regenerate damaged cells, tissues or organs to their full function, such as finding ways for the body to heal wounds faster or to repair bone that has been damaged.

Research strategies can be material-based, cell-based and drug delivery, or combinations of those. Some of the current material-based research in the craniofacial area, for example, uses tiny polymer-based scaffolds that are implanted to promote the growth of damaged bone or periodontal tissue that supports teeth or tooth replacement dental implants.

Project directors and principal investigators at the School of Dentistry are David Kohn, professor in the school’s Department of Biologic and Materials Sciences and also professor of biomedical engineering at the College of Engineering, and William Giannobile, the William K. and Mary Anne Najjar Professor of Dentistry and chair of the Department of Periodontics and Oral Medicine, and professor of biomedical engineering at the College of Engineering.

Laurie McCauley, dean of the School of Dentistry, said the resource center has assembled a strong team poised for important breakthroughs in this quickly evolving field.

“Drs. Kohn and Giannobile have established a multidisciplinary group with a robust plan that will build on Michigan’s success in basic tissue engineering and training to achieve transformative approaches in regenerative medicine,” she said.

Kohn said this three-year phase will be a period of investigating many aspects of each project.

“The purpose of the center is to vet technologies,” he said. “And not only vet them scientifically but vet them clinically: Is this scaffold going to solve a compelling clinical problem? Vet them in terms of manufacturing: Can this be manufactured? Can it be manufactured to FDA standards? Vet them in terms of commercialization: Is anyone going to invest and buy this?

“We might prove in a small clinical study that something is effective, but it’s not going to get out to the masses unless a company or investors decide to pursue the technology. So we’re talking about vetting in all those different sectors.”

Giannobile said U-M is uniquely positioned to lead the center. The funding application notes that U-M is the only university in the country with Top 10-ranked dental, medical and engineering schools on the same contiguous campus, which makes it easier for interdisciplinary collaboration in tissue engineering and regenerative medicine.

“There are so many excellent independent investigators here at U-M with individual grants and patents in regenerative medicine,” Giannobile said. “We feel fortunate that we were able to coalesce many different groups from around the university that could really help spearhead regenerative medicine at Michigan with this type of larger, programmatic grant.

“It’s oral, dental and craniofacial research, but certainly this will serve as a bridge to other parts of the body—the musculoskeletal system, bone regeneration, soft tissue, nerve, other structures—because what we learn in the all-important head and neck area will apply to other areas as well.”

Joining Kohn and Giannobile as project directors and principal investigators are Charles Sfeir and William Wagner of the University of Pittsburgh and David Mooney of Harvard.

The project includes two key private-sector contributors—the McGuire Institute of Houston, with extensive experience in practice-based clinical research in regenerative oral and periodontal medicine, and the Avenues Company of Flagstaff, Ariz., a marketing consulting firm focusing on clinical and business development strategies in regenerative dentistry.

NIDCR is one of 27 institutes and centers under the umbrella of the National Institutes of Health. NIH is part of the Department of Health and Human Services.

The new Michigan and California centers are part of the NIDCR’s Dental, Oral, and Craniofacial Tissue Regeneration Consortium, an initiative designed to shepherd new therapies through preclinical studies and into human clinical trials. The ultimate goal is to develop strategies and devices that could help repair or regenerate damaged tissues such as craniofacial bone, muscle and blood vessels, nerves, teeth and salivary glands.

“By establishing this research consortium, NIDCR seeks to lead national efforts to accelerate the translation of promising dental, oral and craniofacial regenerative medicine therapies into the clinic,” said NIDCR Director Martha Somerman. “The consortium is designed as a model for optimizing translation of scientific advances in this field.”

More information:


One Lab, Three Approaches to Restoring Ovarian Function Ariella Shikanov

By Aimee Balfe

BME Assistant Professor Ariella Shikanov has just received an NSF CAREER award to help fund one of the three approaches her lab is taking to help restore ovarian function in women and girls undergoing treatment for cancer and autoimmune disease that is toxic to the ovaries.

While physicians can freeze a woman’s eggs, allowing her to later have a biologically related child, the process isn’t suitable for some patients, including young girls. It also doesn’t address the issue of ovaries’ endocrine function. “Ovaries are not only about making babies,” says Shikanov, “they also produce estrogen, progesterone, and other hormones that are very important for the health of a woman’s bones, cardiovascular system, and skin.”

“Ovaries are not only about making babies…they also produce estrogen, progesterone, and other hormones that are very important for the health of a woman’s bones, cardiovascular system, and skin.” Shikanov

They’re also essential for enabling girls to go through puberty. Girls who’ve lost ovarian function require synthetic hormones, whose long-term use carries a health risk. In addition, the dosage has to be just right. Too little and the girls won’t grow sufficiently. Too much and the bones’ growth plates close prematurely. Without optimal dosing, the girls are at increased risk for various bone, cardiovascular, and metabolic problems like diabetes and obesity.

The Path to U-M

shikanovShikanov would become captivated by this issue and begin down a road that would lead her from the Hebrew University in Jerusalem to U-M via a postdoctoral fellowship in the lab of Lonnie Shea. Then at Northwestern, and now U-M’s William and Valerie Hall Chair and Professor of BME, Shea had been working on ovarian tissue engineering and needed a postdoc with expertise in polymer synthesis and hydrogel development. Shikanov, a medicinal chemist by training, had the right skill set.

“He told me, ‘Don’t worry; you’ll learn about reproduction,’” she says. Over the next four years, she found herself doing surgeries in mice, looking for ways to make ovarian tissue transplantation more successful, and developing synthetic culture environments for ovarian follicles – the structures that contain immature eggs and are essential to endocrine function.

The latter offered an intriguing engineering challenge. “We had to design a hydrogel that would be soft enough not to kill an ovarian follicle, but rigid enough to support its 3D structure as it matures and expands 100 times in volume,” she says. “It also had to be physiologic, allowing the diffusion of nutrients and oxygen.”

“We had to design a hydrogel that would be soft enough not to kill an ovarian follicle, but rigid enough to support its 3D structure as it matures and expands 100 times in volume” Shikanov

She was deep in this work when U-M announced a cluster-hire position in reproductive biomaterials that precisely matched her expertise. She was hired in 2012, launching a lab that would address ovarian function through three distinct but mutually reinforcing projects.

The Projects

Restoring endocrine function in girls

Shikanov’s first project aims to restore endocrine function in girls with damaged ovaries, allowing them to undergo physiologic puberty. She is developing an implant that encapsulates donor ovarian tissue in an immunoisolating hydrogel. Injected under the skin, it won’t restore fertility but would stimulate the production of estrogen at this critical time.

“Puberty starts in the brain,” says Shikanov. “The hypothalamus secretes a hormone, which stimulates the pituitary gland to secrete follicular stimulating hormone, which tells the ovarian tissue to secrete estrogen. Then the estrogen goes back to the brain, controlling things through a finely tuned loop. This is what allows us to go through puberty, and this why it is so important to have a healthy and functioning ovarian tissue that we aim to engineer.”

With a grant from The Hartwell Foundation, her lab has already demonstrated in mice that the process works and that its longevity is determined by the number of follicles implanted. She plans to move to larger animal models before testing the product in humans.

Understanding how ovarian follicles develop

Shikanov’s second project, for which she won her CAREER award, aims to understand the cell signaling involved in the development of ovarian follicles so she can design better culture systems for harvested tissue.

Harvesting of immature ovarian follicles holds promise for restoring fertility when a woman can’t freeze her eggs – either because she doesn’t have time to undergo ovarian stimulation prior to starting treatment or because she has a hormone-driven cancer where stimulation would be inappropriate. The problem has been getting follicles to survive and mature in culture.

The reason for this, says Shikanov, is that follicles’ essential signaling networks are poorly understood. “Right now, we know that follicles grow best when they’re co-cultured with other follicles and stem cells, but we don’t know why.”

She hopes to remedy this through mechanistic studies of folliculogenesis. Using transcription factor reporters, metabolomics, and systems biology, she aims to reveal the identity, timing and activity pattern of secreted growth factors and transcription factors that allow follicles to grow.

During the project, she plans to continue collaborating with Lonnie Shea, as well as with BME computational modeling expert David Sept, new faculty member Kelly Arnold, and U-M’s metabolomics core, MRC2.

She will start the experimental work in mice, but hopes to move to human tissue in a matter of years. “I want to get to the point where I can take one follicle and say, if I add this list of factors at these concentrations in this timing sequence, I will be able to grow the follicle without adding other follicles or cells,” she says.

Designing an artificial ovary
engineering-ovary
Her final project is the design of an artificial ovary. This involves encapsulating the smallest, primordial follicles in a synthetic polymer that mimics the ovaries’ natural environment with the goal of restoring both fertility and endocrine function. She expects that her mechanistic studies will offer substantial insights to this work.

Shikanov says her research is extremely gratifying, and she enjoys introducing it to young people, especially women, through camps and programs for middle and high schoolers. In addition, her lab is always seeking talented postdocs interested in learning more about biomaterials in reproductive sciences. She can be contacted at shikanov@umich.edu.


New Michigan Regenerative Medicine Center Formed

 
The University of Michigan School of Dentistry is one of 10 institutions in the country that has been selected by the National Institute of Dental and Craniofacial Research (NIDCR) to establish a center that will develop clinical applications in tissue engineering and regenerative medicine that have dental, oral and craniofacial tests.

The Michigan Regenerative Medicine Resource Center, as it’s official known, will be led by Drs. William Giannobile and David Kohn.  Their education and expertise complement each other – Giannobile’s as a clinician/life scientist; Kohn’s as an engineer.  Giannobile chairs the school’s Department of Periodontics and Oral Medicine.  Kohn is a professor in the school’s Department of Biologic and Materials Sciences and a professor in the Department of Biomedical Engineering at the College of Engineering.

“The center will transform how clinicians in the not-too-distant future repair, reconstruct and regenerate dental, oral and craniofacial anomalies in patients due to injury or disease,” Giannobile says.  “In recent years there have been major discoveries and advances in dentistry, medicine, biology, materials science, technology and other fields, and NIDCR wants the Michigan Center and similar centers around the country to find ways to use those advances so clinicians can then apply those discoveries to help their patients.”

Above are three-dimensional printed polymer scaffolds designed to promote bone and periodontal repair in the oral cavity. The design offers the potential to regenerate the different tissues teeth needed to treat teeth that have lost support due to the periodontal disease process. Photo by Jerry Mastey

Above are three-dimensional printed polymer scaffolds designed to promote bone and periodontal repair in the oral cavity. The design offers the potential to regenerate the different tissues teeth needed to treat teeth that have lost support due to the periodontal disease process. Photo by Jerry Mastey

Above are three-dimensional printed polymer scaffolds designed to promote bone and periodontal repair in the oral cavity. The design offers the potential to regenerate the different tissues teeth needed to treat teeth that have lost support due to the periodontal disease process. Photo by Jerry Mastey

Above are three-dimensional printed polymer scaffolds designed to promote bone and periodontal repair in the oral cavity. The design offers the potential to regenerate the different tissues teeth needed to treat teeth that have lost support due to the periodontal disease process. Photo by Jerry Mastey

×

Crucial to achieving that objective, Kohn says, will be establishing teams of multidisciplinary and interdisciplinary specialists from across the University of Michigan, industry and private practice.  “These teams will be dedicated to selecting the most scientifically sound, clinically and commercially applicable strategies to regenerate oral tissues,” he says.

Historically, Kohn says, discoveries in a laboratory have progressed in a linear fashion, that is, they move forward one step at a time before being commercialized and used clinically.  “We want to change that approach,” Kohn adds.  “Our teams will take discoveries that show promise and provide the resources to advance the technologies to apply them more quickly than in the past.”  This approach, he adds, is uniquely suited to Michigan’s broad scientific, clinical and engineering strengths, and interdisciplinary culture.

Giannobile says clinical teams will work with technical advisory groups and data centers to assess what might be feasible clinically.  In the past, he says, scientists and clinicians have not always communicated to take advantages of scientific advances that can be used by dentists in a patient care setting.

Among the groups that will help the Michigan Regenerative Medicine Resource Center will be the Wyss Institute at Harvard, a multidisciplinary research institute that focuses on developing new materials with applications in health care, manufacturing and other areas, and the McGuire Institute in Houston which focuses on delivering clinical applications based on research using new or improved technologies.

The center was established with a $125,000 grant from NIDCR, the first step in what will be a two-step process.  The next step involves submitting a proposal that could possibly lead to funding for as much as $10 million, sometime next summer.

- See more at: http://dent.umich.edu/news/2015/10/14/new-michigan-regenerative-medicine-center-formed#sthash.1i4hOOSf.dpuf