Scientists from the Helmholtz Zentrum München, Germany, were able to describe in detail the pathways of intestinal stem cell differentiation. Understanding this process will help create specific early treatments for endocrine dysfunction and may also be a promising regenerative approach to diabetes therapy.
The gut, like the digestive and largest endocrine system of the body, plays a central role in energy regulation and glucose homeostasis. Its main functions are performed by specialized cells that are constantly generated and renewed every 3-4 days from intestinal stem cells.
For example, the so-called enteroendocrine cells produce more than 20 different types of hormones that send signals to the brain and pancreas to regulate, for example, appetite, food intake, gastric emptying, and insulin secretion by beta cells in the pancreas.
Another important function of the intestine is performed by the so-called Paneth cells, which produce defensins and protect against infection by pathogens. Therefore, it should come as no surprise that gut dysfunction is associated with a myriad of diseases such as chronic inflammation, colorectal cancer, and diabetes, which affect millions of people around the world.
Eliminating endocrine dysfunction at an early stage by stimulating the formation of specific enteroendocrine cells from intestinal stem cells may be a promising regenerative approach for diabetes therapy.
For this, however, a detailed understanding of the hierarchy of intestinal stem cell clones and the signals that regulate the formation of various types of intestinal cells is important. Heiko Lickert, Ph.D., and his research team in their new work aimed to solve this problem. The team’s findings were published in the journal Nature Cell Biology.
The researchers say the main goal of their research is to better understand how intestinal stem cells are constantly renewing and giving rise to specialized cell types. For this, the single-cell transcriptome analysis was used, which analyzes gene expression in individual cells.
“Thus, we are now able to describe potential progenitor populations for each intestinal cell, and we have shown that for every lineage intestinal stem cells give rise to unipotent lineage progenitors”, – first author Anika Böttcher, Ph.D., noted. “Furthermore, we identified a specific intestinal stem cell niche signal pathway (called Wnt/planar cell polarity pathway) regulating intestinal stem cell self-renewal and lineage decisions”.
“This is very important, as we know that intestinal stem cells can indefinitely renew and maintain the gut function and tissue barrier. Those are 6 meters of epithelium and more than 100 million cells generated every day in humans. Moreover, these cells differentiate into every single cell type. The risk of failure in this self-renewal or lineage specification process to result in a chronic disease therefore is quite high.”
During the experiment, the researchers combined the method of labeling intestinal cells of various reporter lines of mice with the analysis of gene expression of both the entire genome and single cells to determine the origin of intestinal stem cells.
Together with Fabian Theis, Ph.D., and his team of computer biologists from the Helmholtz Munich and the Technical University of Munich, they determined the profiles of 60,000 intestinal cells, using newly developed machine learning methods to automatically identify clone line branching and key factors that influence gene expression.
This study challenges current paradigms and we advanced our understanding of intestinal stem cell self-renewal, heterogeneity, and lineage recruitment
We can use this basic knowledge to map what happens to intestinal stem cell lineage allocation and differentiation during chronic disease. Insights from this will put us in place to develop specific therapies for these diseases by targeting lineage progenitors for example to regenerate the formation of specific cells that are lost during disease progression or to identify and eradicate intestinal cancer stem cells. Specifically, at our institute, we will focus our efforts on diabetes.
“This study challenges current paradigms and we advanced our understanding of intestinal stem cell self-renewal, heterogeneity and lineage recruitment”, – Dr. Lickert said.
“We can use this basic knowledge to map what happens to intestinal stem cell lineage allocation and differentiation during chronic disease. Insights from this will put us in place to develop specific therapies for these diseases by targeting lineage progenitors for example to regenerate the formation of specific cells that are lost during disease progression. Specifically, at our institute, we will focus our efforts on diabetes”.