Nav: Home

Mass. General team creates functional, stem-cell-derived small bowel segments

October 10, 2017

Using human induced pluripotent stem cells (iPSCs), a Massachusetts General Hospital research team has bioengineered functional small intestine segments that, when implanted into rats, were capable of deliver nutrients into the bloodstream. The investigators describe their accomplishment in the online journal Nature Communications.

"In this study we have been able to bridge the gap between differentiation of single cells - driving stem cells to become a specific cell type - and the generation of tissue that shows a higher level of function - in this instance vascular perfusion and nutrient absorption," says Harald Ott, MD of the MGH Department of Surgery and the Center for Regenerative Medicine, senior author of the report. "While previous studies have reported successful differentiation of organoids - millimeter-small units of tissue - from iPSCs, we describe a technology that enables these smaller units of tissue to form larger-scale grafts that someday could be used as implanted replacement organs.

Several serious gastrointestinal diseases, including Crohn's disease, may lead to removal of all or part of the small intestine, leading to a condition called short bowel syndrome. While it sometimes can be treated with special diets, many patients need to rely on intravenous nutrition. While small bowel transplantation is a feasible treatment option, its availability is very limited because of the organ shortage. For example, while 127 transplants were performed in the U.S. in 2015, as of October 4, 2017, 273 patients remained on the waiting list.

As with previous studies from Ott's team, this one utilizes a procedure he developed in 2008 for stripping the living cells from a donor organ with a detergent solution and then repopulating the remaining extracellular matrix scaffold with organ-appropriate types of cells. His team has decellularized animal kidneys, lungs and hearts; generated functional rat kidneys and lungs, and last year regenerated functional heart muscle in decellularized human hearts. In this study, the MGH team used that same approach to decellularize 4 cm segments of rat small intestine and confirmed the applicability of the procedure to larger animals in segments of pig intestine.

While the decellularized small intestine would provide the structural scaffold for both the complex tissue of the interior lining and the vascular channels, repopulating the scaffold requires the delivery, engraftment and maturation of two types of cells - epithelial cells for the intestinal lining and endothelial cells for the blood vessels - in the right locations. Generation of epithelial tissue began with human iPSCs that were differentiated into intestinal precursor cells and then seeded into the interior of the decellularized segments, which then were cultured. Two weeks later, after formation of the epithelial layer, human endothelial cells were seeded into the vascular channels; and the segments placed in a perfusion bioreactor system for further maturation.

Several days later, in vitro testing of the segments confirmed blood passage through the repopulated vasculature and showed that the reconstituted intestinal tissue could transfer glucose and fatty acids from the interior of segments into the blood vessels. The repopulated epithelial cells lining the segments had the same polarized structure - with the proteins lining cellular membranes on the interior of the segments differing from those at the base of the cells - seen in naturally occurring intestinal epithelium.

A few of the segments were sutured to the carotid arteries and jugular veins of immunodeficient rats. The vasculature of the segments was immediately perfused with blood, and four weeks later injections of either glucose or fatty acids into the segments resulted in increased levels in the animals' bloodstreams, confirming absorption of the nutrients. In addition, specific types of cells normally found in the intestinal lining that had not appeared while the segment were cultured did after implantation into the living animals, implying continued maturation of the tissue.

"Our in vivo experiments showed that human iPSCs differentiated towards an intestinal fate can be assembled into an intestinal graft with a high level of organization and connected to a recipient's vasculature to enable nutrient absorption after transplantation," says Ott, who is an associate professor of Surgery at Harvard Medical School. "The next steps will be to further mature these grafts and to scale the construct to a human size, so that someday we may be able to provide a more accessible alternative to small bowel transplantation for patients with short bowel syndrome - ideally growing 'on-demand' patient-specific grafts that would not require immunosuppressive drugs."
-end-
Kentaro Kitano, MD, of the MGH Department of Surgery and the University of Tokyo, is lead author of the Nature Communications paper. Additional co-authors are Dana Schwartz, MD, Haiyang Zhou, MD, Sarah Gilpin, PhD, Xi Ren, PhD, Douglas Mathisen, MD, and Allan Goldstein, MD, MGH Surgery; Gregory Wojtkiewicz, MS, MGH Center for Systems Biology; and Cesar Sommer, PhD, Amalia Capilla, PhD, and Gustavo Mostoslavsky, MD, PhD, Boston University School of Medicine. Support for the study includes National Institutes of Health Director's New Innovator Award DP2 OD008749-01, the Charles and Sara Fabrikant MGH Research Scholar Award, and a grant from the Mendez National Institute of Transplantation Foundation.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $850 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2017 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

Related Blood Vessels Articles:

Study: Use of prefabricated blood vessels may revolutionize root canals
Researchers at OHSU in Portland, Oregon, have developed a process by which they can engineer new blood vessels in teeth, creating better long-term outcomes for root canal patients and clinicians.
New findings on formation and malformation of blood vessels
In diseases like cancer, diabetes, rheumatism and stroke, a disorder develops in the blood vessels that exacerbates the condition and obstructs treatment.
Targeting blood vessels to improve cancer immunotherapy
EPFL scientists have improved the efficacy of cancer immunotherapy by blocking two proteins that regulate the growth of tumor blood vessels.
Reprogrammed blood vessels promote cancer spread
Tumor cells use the bloodstream to spread in the body.
Neurons modulate the growth of blood vessels
A team of researchers at Karlsruhe Institute of Technology shake at the foundations of a dogma of cell biology.
Sensor for blood flow discovered in blood vessels
The PIEZO1 cation channel translates mechanical stimulus into a molecular response to control the diameter of blood vessels.
Blood vessels control brain growth
Blood vessels play a vital role in stem cell reproduction, enabling the brain to grow and develop in the womb, reveals new UCL research in mice.
No blood vessels without cloche
After 20 years of searching, scientists discover the mystic gene controlling vessel and blood cell growth in the embryo.
New way of growing blood vessels could boost regenerative medicine
Growing tissues and organs in the lab for transplantation into patients could become easier after scientists discovered an effective way to produce three-dimensional networks of blood vessels, vital for tissue survival yet a current stumbling block in regenerative medicine.
Regenerating blood vessels gets $2.7 million grant
Biomedical engineers in the Cockrell School of Engineering at The University of Texas at Austin have received $2.7 million in funding to advance a treatment that regenerates blood vessels.

Related Blood Vessels Reading:

Blood-Vessel Surgery and Its Applications;
by Charles Claude B 1880 Guthrie (Creator)

Blood Vessels like a Teenager: Insider-cures against atherosclerosis
by Christian Meyer-Esch (Author)

Inflammatory Diseases of Blood Vessels
by Gary S. Hoffman (Editor), Cornelia M. Weyand (Editor), Carol A. Langford (Editor), Jorg J. Goronzy (Editor)

Heart, Lungs and Blood Vessels - Their Descriptions, Functions and Diseases: Useful Heart, Lung and Blood Vessel Information – Condensed For Easy Learning (0001)

Anatomy flashcards: Meninges & blood vessels of the brain: Learn all arteries, veins, organs, tissues, bones and nerves on the go (Kenhub Flashcards Book 1)
by Kenhub

The Blood Vessels of the Human Skin and Their Responses (The Classics of Medicine Library)
by Thomas Lewis (Author)

The Fluid Mechanics of Large Blood Vessels (Cambridge Monographs on Mechanics)
by T. J. Pedley (Author)

Inflammatory Diseases of Blood Vessels
by Gary S. Hoffman (Author), Cornelia M. Weyand (Author)

Little Book for Heart and Blood Vessel Health: What is my risk for heart attack or another vascular event? How do I achieve goal?
by Philip H. Frost M.D. (Author)

Blood Pressure / Diabetes Log Book: Daily Logbook for Recording Blood Glucose Levels, Tracking BP, Water Intake and Weight Journal for Heart Patients With Congestive Heart Failure and/or Diabetes
by Tracking Health Stats Journals (Author)

Best Science Podcasts 2018

We have hand picked the best science podcasts for 2018. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Why We Hate
From bullying to hate crimes, cruelty is all around us. So what makes us hate? And is it learned or innate? This hour, TED speakers explore the causes and consequences of hate — and how we can fight it. Guests include reformed white nationalist Christian Picciolini, CNN commentator Sally Kohn, podcast host Dylan Marron, and writer Anand Giridharadas.
Now Playing: Science for the People

#482 Body Builders
This week we explore how science and technology can help us walk when we've lost our legs, see when we've gone blind, explore unfriendly environments, and maybe even make our bodies better, stronger, and faster than ever before. We speak to Adam Piore, author of the book "The Body Builders: Inside the Science of the Engineered Human", about the increasingly amazing ways bioengineering is being used to reverse engineer, rebuild, and augment human beings. And we speak with Ken Thomas, spacesuit engineer and author of the book "The Journey to Moonwalking: The People That Enabled Footprints on the Moon" about...