SCIENTISTS GENERATE FIRST HUMAN TISSUE IN L;AB WITH STEM CELLS
Scientists used
pluripotent stem cells to generate functional, three-dimensional human stomach
tissue in a laboratory -- creating an unprecedented tool for researching the
development and diseases of an organ central to several public health crises,
ranging from cancer to diabetes.
Scientists at
Cincinnati Children's Hospital Medical Center report Oct. 29 in Nature they
used human pluripotent stem cells -- which can become any cell type in the body
-- to grow a miniature version of the stomach. In collaboration with
researchers at the University of Cincinnati College of Medicine, they used
laboratory generated mini-stomachs (called gastric organoids) to study
infection by H. pylori bacteria, a major cause of peptic ulcer disease and
stomach cancer.
This first-time
molecular generation of 3D human gastric organoids (hGOs) presents new
opportunities for drug discovery, modeling early stages of stomach cancer and
studying some of the underpinnings of obesity related diabetes, according to
Jim Wells, PhD, principal investigator and a scientist in the divisions of
Developmental Biology and Endocrinology at Cincinnati Children's.
It also is the first
time researchers have produced 3D human embryonic foregut -- a promising
starting point for generating other foregut organ tissues like the lungs and
pancreas, he said.
"Until this
study, no one had generated gastric cells from human pluripotent stem cells
(hPSCs)," Wells said. "In addition, we discovered how to promote
formation of three-dimensional gastric tissue with complex architecture and
cellular composition."
This is important
because differences between species in the embryonic development and
architecture of the adult stomach make mouse models less than optimal for
studying human stomach development and disease, Wells added.
Researchers can use
human gastric organoids as a new discovery tool to help unlock other secrets of
the stomach, such as identifying biochemical processes in the gut that allow
gastric-bypass patients to become diabetes-free soon after surgery before
losing significant weight. Obesity fueled diabetes and metabolic syndrome are
an exploding public health epidemic. Until now, a major challenge to addressing
these and other medical conditions involving the stomach has been a relative lack
of reliable laboratory modeling systems to accurately simulate human biology,
Wells explained.
The key to growing
human gastric organoids was to identify the steps involved in normal stomach
formation during embryonic development. By manipulating these normal processes
in a petri dish, the scientists were able to coax pluripotent stem cells toward
becoming stomach. Over the course of a month, these steps resulted in the
formation of 3D human gastric organoids that were about 3mm (1/10th of an inch)
in diameter. Wells and his colleagues also used this approach to identify what
drives normal stomach formation in humans with the goal of understanding what
goes wrong when the stomach does not form correctly.
Along with study first
author Kyle McCracken, an MD/PhD graduate student working in Wells' laboratory,
and Yana Zavros, PhD, a researcher at UC's Department of Molecular and Cellular
Physiology, the authors report they were impressed by how rapidly H. pylori
bacteria infected stomach epithelial tissues.
Within 24 hours, the
bacteria had triggered biochemical changes to the organ, according to
McCracken. The human gastric organoids faithfully mimicked the early stages of
gastric disease caused by the bacteria, including the activation of a cancer
gene called c-Met and the rapid spread of infection in epithelial tissues.
Another significant
part of the team's challenge has been the relative lack of previous research
literature on how the human stomach develops, the authors said. Wells said the
scientists had to use a combination of published work, as well as studies from
his own lab, to answer a number of basic developmental questions about how the
stomach forms. Over the course of two years, this approach of experimenting
with different factors to drive the formation of the stomach eventually
resulted in the formation of 3D human gastric tissues in the petri dish.
Wells emphasized
importance of basic research for the eventual success of this project, adding,
"This milestone would not have been possible if it hadn't been for
previous studies from many other basic researchers on understanding embryonic
organ development."
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