Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

True to type: From human biopsy to complex gut physiology on a chip

14.02.2018

Organ Chip technology using donor-derived human intestinal cells offers advantages over organoids and creates new opportunities for personalized medicine

The small intestine is the main site where we digest and absorb nutrients and minerals from food, and it is also a place where many intestinal infections occur and digestive and inflammatory disorders manifest themselves. To better understand the intestine in its normal and pathological states, researchers have created "organoids" by isolating intestinal stem cells from human biopsy samples. These organoids form all of the cell types present in human intestine, but they grow as cysts surrounded by thick extracellular matrix gels with their "apical" cell surface (which is normally exposed to the content of the gut) facing an enclosed lumen. This prevents the study of dynamic processes involving the intestinal barrier, including nutrient and drug transport, as well as its interactions with the microbiome. In addition, organoids lack a vasculature and the mechanical movements caused by normal peristalsis and blood flow, which are vital for many processes in the gut, including its regeneration and control of bacterial overgrowth.


This image shows villi-like extensions that primary small intestinal cells protrude into the lumen of the epithelial channel of the chip.

Credit: Wyss Institute at Harvard University

In an effort to overcome these limitations, a team at the Wyss Institute for Biologically Inspired Engineering led by its Founding Director, Donald Ingber, M.D., Ph.D., had previously engineered a microfluidic "Organ-on-a-Chip" (Organ Chip) culture device in which cells from a human intestinal cell line originally isolated from a tumor were cultured in one of two parallel running channels, separated by a porous matrix-coated membrane from human blood vessel-derived endothelial cells in the adjacent channel. Although this human Gut Chip recreated the villus epithelium of normal intestine and enabled new insights into how flow and cyclic peristalsis affects intestinal differentiation and function, it could not be used to study processes that relied on normal intestinal cells from individual donors, which, for example, is crucial for studying patient-specific responses for personalized medicine.

In a new study, published in Scientific Reports, Ingber's team now removes these roadblocks. "We are now able to leverage the organoid approach to isolate intestinal stem cells from human biopsies, but we break up the organoids and culture the patient-specific cells within our Organ Chips where they spontaneously form intestinal villi oriented towards the channel lumen, and the epithelium in close apposition to human intestinal microvascular endothelium," said Ingber, who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS) and the Vascular Biology Program at Boston Children's Hospital, as well as Professor of Bioengineering at Harvard's John A. Paulson School of Engineering and Applied Sciences (SEAS). "This approach presents a new stepping stone for the investigation of normal and disease-related processes in a highly personalized manner, including the transport of nutrients, digestion, different intestinal disorders, and intestinal interactions with commensal microbes as well as pathogens."

... more about:
»Harvard »Wyss »biopsy »epithelium »intestine »stem cells

The team collaborated with David Breault's laboratory at Boston Children's Hospital to build an organoid culture step into their procedure to isolate normal intestinal stem cells and increase their cell numbers. The resulting organoids could either be banked for future use or immediately fragmented and seeded into the "epithelial" channels of multiple Organ Chips where they were further matured by flowing specialized culture medium and applying mechanical stimulation to the channels to mimic physiological peristalsis-like motions. The epithelium's maturation into a villus intestinal epithelium with long finger-like extensions was helped along by co-culturing human intestinal microvascular endothelial cells on the opposite side of the shared matrix-coated porous membrane in the "vascular" channel where they assembled a surrogate blood vessel with a hollow lumen through which feeding medium was flowed.

Thus, combining two of the most advanced technologies in the field of tissue engineering ? organoid culture and Organ Chips ? allowed the generation of intestine tissues and organ-level structures lined by human donor-specific cells with morphology, composition, and function strongly resembling that of the duodenal region of normal small intestine. "Because the primary Small Intestine Chip recapitulates the physical microenvironment that cells experience inside the human body, such as fluid flow and cyclic peristalsis-like stretching motions, it exhibits a genome-wide gene expression profile that comes closer to its in vivo counterpart than that of the same intestinal cells grown as 3D organoids," said first-author Magdalena Kasendra, Ph.D., a former Postdoctoral Fellow on Ingber's team and now Principal Scientist at Emulate, Inc. in Boston.

Along with intestinal stem cells, the team identified differentiated nutrient-digesting and absorbing enterocytes, mucus-producing Goblet cells, hormone-secreting enteroendocrine cells, and microbiome-regulating and sensing Paneth cells, and they performed a series of assays that confirmed their functions. As the small intestinal microenvironment can be maintained for weeks in continuously perfused Organ Chips, they enable both short and longer-term studies whose observations can be related back to the health and physiology of individual donors.

Ingber's team is applying the same approach now to different regions of the intestine -- duodenum, jejunum, ileum, and colon -- whose functions and disease vulnerabilities differ from one another. This approach is also being used to reverse engineer even more complex gut environments by integrating other cell types, such as immune cells, neuronal cells, and commensal microbes into the device. "In the future, such efforts could allow us to much better understand human-microbiome interactions, model malnutrition disorders and inflammatory diseases of the gut, and perform personalized drug testing," said co-first author Alessio Tovaglieri, a Graduate Student at the Department of Health Science and Technology at ETH Zurich in Switzerland, who performs his thesis work on Ingber's team.

###

Additional authors on the study are David Breault, M.D., Ph.D., Assistant Professor at HMS and Research Associate at Boston Children's Hospital; Alexandra Sontheimer-Phelps, Sasan Jalili-Firoozinezhad, Amir Bein, Ph.D., Angeliki Chalkiadaki, Ph.D., and William Scholl at the Wyss Institute; Cheng Zhang, Ph.D., and Hu Li, Ph.D., from Mayo Clinic College of Medicine in Rochester, Minesota; and Camilla Richmond, M.D., and Hannah Rickner from Boston Children's Hospital. It was funded by Harvard's Wyss Institute for Biologically Inspired Engineering, the Defense Advanced Research Projects Agency, Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, National Institute of Health, and the Bill and Melinda Gates Foundation.

MULTIMEDIA AVAILABLE

PRESS CONTACT

Wyss Institute for Biologically Inspired Engineering at Harvard University
Benjamin Boettner
617-432-8232
benjamin.boettner@wyss.harvard.edu

MULTIMEDIA CONTACT

Wyss Institute for Biologically Inspired Engineering at Harvard University
Seth Kroll
617-432-7758
seth.kroll@wyss.harvard.edu

The Wyss Institute for Biologically Inspired Engineering at Harvard University uses Nature's design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world. Wyss researchers are developing innovative new engineering solutions for healthcare, energy, architecture, robotics, and manufacturing that are translated into commercial products and therapies through collaborations with clinical investigators, corporate alliances, and formation of new startups. The Wyss Institute creates transformative technological breakthroughs by engaging in high risk research, and crosses disciplinary and institutional barriers, working as an alliance that includes Harvard's Schools of Medicine, Engineering, Arts & Sciences and Design, and in partnership with Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Boston Children's Hospital, Dana-Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, Charité - Universitätsmedizin Berlin, University of Zurich and Massachusetts Institute of Technology.

Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including seven members of the National Academy of Sciences, 11 members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's today is the number one pediatric hospital in the nation, with a 415-bed comprehensive center for pediatric and adolescent health care. Boston Children's is also the pediatric teaching affiliate of Harvard Medical School.

Benjamin Boettner | EurekAlert!

Further reports about: Harvard Wyss biopsy epithelium intestine stem cells

More articles from Medical Engineering:

nachricht An MRI technique has been developed to improve the detection of tumors
03.06.2020 | Moscow Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies

nachricht High-resolution 3D view inside breast tumors with opto-acoustic mesoscopy
27.05.2020 | Technische Universität München

All articles from Medical Engineering >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Restoring vision by gene therapy

Latest scientific findings give hope for people with incurable retinal degeneration

Humans rely dominantly on their eyesight. Losing vision means not being able to read, recognize faces or find objects. Macular degeneration is one of the major...

Im Focus: Small Protein, Big Impact

In meningococci, the RNA-binding protein ProQ plays a major role. Together with RNA molecules, it regulates processes that are important for pathogenic properties of the bacteria.

Meningococci are bacteria that can cause life-threatening meningitis and sepsis. These pathogens use a small protein with a large impact: The RNA-binding...

Im Focus: K-State study reveals asymmetry in spin directions of galaxies

Research also suggests the early universe could have been spinning

An analysis of more than 200,000 spiral galaxies has revealed unexpected links between spin directions of galaxies, and the structure formed by these links...

Im Focus: New measurement exacerbates old problem

Two prominent X-ray emission lines of highly charged iron have puzzled astrophysicists for decades: their measured and calculated brightness ratios always disagree. This hinders good determinations of plasma temperatures and densities. New, careful high-precision measurements, together with top-level calculations now exclude all hitherto proposed explanations for this discrepancy, and thus deepen the problem.

Hot astrophysical plasmas fill the intergalactic space, and brightly shine in stellar coronae, active galactic nuclei, and supernova remnants. They contain...

Im Focus: Biotechnology: Triggered by light, a novel way to switch on an enzyme

In living cells, enzymes drive biochemical metabolic processes enabling reactions to take place efficiently. It is this very ability which allows them to be used as catalysts in biotechnology, for example to create chemical products such as pharmaceutics. Researchers now identified an enzyme that, when illuminated with blue light, becomes catalytically active and initiates a reaction that was previously unknown in enzymatics. The study was published in "Nature Communications".

Enzymes: they are the central drivers for biochemical metabolic processes in every living cell, enabling reactions to take place efficiently. It is this very...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Dresden Nexus Conference 2020: Same Time, Virtual Format, Registration Opened

19.05.2020 | Event News

Aachen Machine Tool Colloquium AWK'21 will take place on June 10 and 11, 2021

07.04.2020 | Event News

International Coral Reef Symposium in Bremen Postponed by a Year

06.04.2020 | Event News

 
Latest News

New image of a cancer-related enzyme in action helps explain gene regulation

05.06.2020 | Life Sciences

Silicon 'neurons' may add a new dimension to computer processors

05.06.2020 | Physics and Astronomy

Protecting the Neuronal Architecture

05.06.2020 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>