Blueprints for how human kidneys form their filtering units

Date:
August 23, 2021
Source:
Keck School of Medicine of USC
Summary:
A team of scientists has conducted a comprehensive analysis
reconstructing how kidneys form their filtering units, known
as nephrons.

The team studied hundreds of human and mouse nephrons at various
points along their typical developmental trajectories, comparing
important processes that have been conserved during the nearly 200
million years of evolution since humans and mice diverged from
their common mammalian ancestor. The study details the similar
genetic machinery that underpins nephron formation in humans and
mice, enabling other groups of scientists to follow the logic of
these developmental programs to make new types of kidney cells.



FULL STORY ==========================================================================
When it comes to building a kidney, only nature possesses the complete
set of blueprints. But a USC-led team of scientists has managed to borrow
some of nature's pages through a comprehensive analysis of how kidneys
form their filtering units, known as nephrons.


========================================================================== Published in the journal Developmental Cell, the study from Andy
McMahon's lab in the Department of Stem Cell Biology and Regenerative
Medicine at USC was led by Nils Lindstro"m, who started the research
as a postdoctoral fellow and is now an assistant professor in the same department. The study also brought in the expertise of collaborators
from Princeton University and the University of Edinburgh in the UK.

The team traced the blueprints for how cells interact to lay the
foundations of the human kidney, and how abnormal developmental processes
could contribute to disease. Their findings are publicly available as
part of the Human Nephrogenesis Atlas, which is a searchable database
showing when and where genes are active in the developing human kidney,
and predicting regulatory interactions going on in developing cell types.

"There's only one way to build a kidney, and that's nature's way,"
said McMahon, who is the director of the Eli and Edythe Broad Center
for Regenerative Medicine and Stem Cell Research at USC. "Only by
understanding the logical framework of normal embryonic development
can we improve our ability to synthesize cell types, model disease and ultimately build functional systems to replace defective kidneys."
To reconstruct nature's molecular and cellular blueprints, the team
studied hundreds of human and mouse nephrons at various points along
their typical developmental trajectories. This allowed the researchers
to compare important processes that have been conserved during the nearly
200 million years of evolution since humans and mice diverged from their
common mammalian ancestor.

The study details the similar genetic machinery that underpins nephron formation in humans and mice, enabling other groups of scientists to
follow the logic of these developmental programs to make new types of
kidney cells. All told, there are at least 20 specialized cell types that
form the kidney's intricate tubular network, which helps maintain the
body's fluid and pH balance, filter the blood, and concentrate toxins
into the urine for excretion.

"By generating detailed views of the beautifully complex process by which
human nephrons form, we aim to enhance our understanding of development
and disease, while guiding efforts to build synthetic kidney structures,"
said Lindstro"m.

The scientists were also able to determine the precise positions of
expressed genes with known roles in Congenital Abnormalities of the Kidney
and Urinary Tract (CAKUT). In specific types of cells, the researchers identified networks of interacting genes. Based on these associations,
the team predicted new candidate genes to explore in CAKUT and other
kidney diseases.

"Our approach of inferring spatial coordinates for genes expressed in individual cells could be widely used to create similar atlases of other developing organ systems -- something that is an important focus of many research groups around the world," said Lindstro"m. "The study exemplifies
the impact of collaborative science bringing together expertise across
the US and Europe to connect developmental anatomy with cutting-edge
molecular, computational and microscopy tools." Additional co-authors
are: Riana K. Parvez, Andrew Ransick, Guilherme De Sena Brandine, Jinjin
Guo, Tracy Tran, Albert D. Kim, Brendan H. Grubbs, Matthew E.

Thornton, Jill A. McMahon, Seth W. Ruffins, and Andrew D. Smith from USC; Rachel Sealfon, Xi Chen, and Jian Zhou from the Flatiron Institute and Princeton University; Alicja Tadych from Princeton University; Aaron
Watters, Aaron Wong, and Elizabeth Lovero from the Flatiron Institute;
Bill Hill from the University of Edinburgh; and Chris Armit the University
of Edinburgh and BGI Hong Kong.

Fifty percent of the research was supported by federal funds from
the National Institutes of Health (DK054364, DK110792, U24DK100845,
UGDK114907, U2CDK114886, and UH3TR002158). Additional support came from
the California Institute for Regenerative Medicine (LA1-06536), and the
Genetic Networks program of the Canadian Institute for Advanced Research (CIFAR).

========================================================================== Story Source: Materials provided by
Keck_School_of_Medicine_of_USC. Original written by Cristy Lytal. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Nils O. Lindstro"m, Rachel Sealfon, Xi Chen, Riana K. Parvez, Andrew
Ransick, Guilherme De Sena Brandine, Jinjin Guo, Bill Hill, Tracy
Tran, Albert D. Kim, Jian Zhou, Alicja Tadych, Aaron Watters, Aaron
Wong, Elizabeth Lovero, Brendan H. Grubbs, Matthew E. Thornton,
Jill A.

McMahon, Andrew D. Smith, Seth W. Ruffins, Chris Armit, Olga G.

Troyanskaya, Andrew P. McMahon. Spatial transcriptional mapping
of the human nephrogenic program. Developmental Cell, 2021; 56
(16): 2381 DOI: 10.1016/j.devcel.2021.07.017 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210823125833.htm

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