Cilia-free stem cells offer a new path to the study of rare diseases

Cilia-free stem cells offer a new path to the study of rare diseases ...

ciliopathies polycystic kidney disease are a number of rare diseases that have arisen from cilia defects. These are the tiny hairlike structures on the surface of almost every cell type. The specific molecular-level limitations in cilia that have caused these diseases are poorly understood.

In a novel experiment, scientists eliminated or deleted the cilia in a minority 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 findings from the journalNature Biomedical Engineering were published on April 27.

We are attempting to understand what cilia does, so we ablated them from these cells, according to Benjamin Freedman, who is a graduate of UW Medicine. We wanted to see if the cells would re-create symptoms of ciliopathy without the cilia. After turning 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 are a powerful new tool for understanding this group of diseases, which can be used to guide therapy development, according to Freedman, an associate professor of medicine at the University of Washington School of Medicine in Seattle.

The cilia is described as cellular compartments where important proteins are connected as if in a Zoom meeting, to make decisions that guide a cell 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 with its own set of partially overlapping symptoms at birth. Polycystic kidney disease (PKD) is a common practice, which affects about 1 in 500 people and causes clinical difficulties typically later in life.

Because ciliopathies affect many organs, pluripotent stem cells, which may become any tissue in the body, might offer a one-stop shop to study these diseases.

Freedman and his colleagues sought to understand what would happen in their subsequent transformation into tissues and organoids as it unfolded. As it progressed, the cilia-free stem cells appeared to be normal, but were not able 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. They struggled to transform into anything sophisticated. One lesson from this is that the cilia aids cells in their final phase of development.

The first time in 2000, PKD could be determined due to cilia defects, but the mechanism of damage that causes cysts to form has escaped scientists. By establishing cilia-free stem cells that harbor disease, according to Freedman, the researchers now have a tool to test and compare molecular actions in the cilia.

By comparing cells that are completely lacking cilia to cells that have cilia but do not have PKD genes, we have a broad spectrum of cell types that should allow us to deduce what''s happening among the molecules involved. For over 30 years, we''ve learned how specific these genetic molecules are causing to create PKD.

You may also like: