Cilia-free stem cells offer new path to study rare diseases
Creating a novel population of mutant tissues helps scientists deduce the cause of polycystic kidney disease and other cilia-linked illnesses

Date:
May 2, 2022
Source:
University of Washington School of Medicine/UW Medicine
Summary:
A group of rare diseases called ciliopathies -- polycystic kidney
disease notable among them -- emerge from defects in cilia. These
are the tiny hairlike structures on the surface of almost every
cell type. Scientists experimentally 'knocked out,' or genetically
deleted, the cilia in a population of otherwise normal human
pluripotent stem cells.

Subsequently, human tissues and mini-organ structures (organoids)
derived from these cilia-free stem cells manifested ciliopathy-like
symptoms, such those seen in polycystic kidney disease or in
certain problems in brain development.



FULL STORY ==========================================================================
A group of rare diseases called ciliopathies -- polycystic kidney disease notable among them -- emerge from defects in cilia. These are the tiny
hairlike structures on the surface of almost every cell type. The specific molecular- level disruptions in cilia that trigger these diseases are
poorly understood.


==========================================================================
In a novel experiment, scientists "knocked out," or deleted, the
cilia in a population of otherwise normal human pluripotent stem
cells. Subsequently, human tissues and mini-organ structures (organoids) derived from these cilia- free stem cells manifested ciliopathy-like
symptoms.

The journal Nature Biomedical Engineering published the findings April 27.

"We are trying to understand what cilia do, so we ablated them from
these cells," said Benjamin Freedman, whose lab at UW Medicine led
the work. "We wanted to see if the cells would re-create symptoms of
ciliopathy without the cilia. Sure enough, when we turned the cells into tissues and organoids (tissue-like structures), they re-created polycystic kidney disease and problems with brain development." The cilia-knockout
stem cells "represent a powerful new tool for understanding this group
of diseases, which can be used to guide therapy development," said
Freedman, an associate professor of medicine, Division of Nephrology at
the University of Washington School of Medicine in Seattle.

He described cilia as cellular compartments where important proteins
are brought together, as if in a Zoom meeting, to make decisions that
guide a cell's development. Without the meeting room, these proteins
can't talk to each other and cell-development decisions are not made.

There are at least 15 ciliopathies, each rare in terms of population
prevalence and each with its own constellation of partially overlapping symptoms.

Ciliopathies frequently present at birth; an exception is polycystic
kidney disease (PKD), which affects about 1 in 500 people and causes
clinical problems mostly later in life.

Because ciliopathies affect many organs, pluripotent stem cells, which
can turn into any tissue in the body, could offer a "one-stop shop"
to study these diseases.

In removing cilia from human pluripotent stem cells, Freedman and his colleagues sought to understand what would happen in their subsequent transformation into tissues and organoids. As it happened, the cilia-free
stem cells appeared normal but were unable to fully realize new forms.

"It was surprising to me that, at a certain point after they were turning
into tissues, they seemed to break down," Freedman said. "They struggled
to transform into anything sophisticated. I think one lesson from this is
that the cilia help get cells through their final stage of development."
It was first reported in 2000 that PKD could stem from defects in cilia,
but the mechanism of damage that causes cysts to form has escaped
scientists. By creating cilia-free stem cells that harbor disease,
Freedman said, the researchers now have a framework with which to test
and compare molecular actions in the cilia.

"By comparing cells that totally lack cilia to cells that possess cilia
but lack PKD genes, as well as to normal cells, we have the whole range
of cell types that should enable us to deduce what's going on among the molecules involved. For almost 30 years we've known the genes involved in
PKD -- even before we knew that cilia were implicated. Hopefully having
these distinct cell types will enable us to figure out what specific
disruption these genetic molecules are causing to create PKD."

========================================================================== Story Source: Materials provided by University_of_Washington_School_of_Medicine/UW_Medicine.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Nelly M. Cruz, Raghava Reddy, Jose' L. McFaline-Figueroa,
Christine Tran,
Hongxia Fu, Benjamin S. Freedman. Modelling ciliopathy phenotypes in
human tissues derived from pluripotent stem cells with genetically
ablated cilia. Nature Biomedical Engineering, 2022; 6 (4): 463 DOI:
10.1038/s41551-022-00880-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/05/220502120501.htm

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