How stem cells retain their stem” ness: The science of staying uncommitted

Aditi Jain

Since their initial discovery several decades ago, stem cells have faced intensive study due to their potential medical applications and fascinating biology. A question that has long interested scientists is how do stem cells continue to remain in an undifferentiated or uncommitted’ state, unlike every other cell type in the body? Now, a new study from researchers at the National Centre for Cell Science (NCCS) sheds light on this unique problem.

Phase image of embryoid bodies (EBs) formed from mouse embryonic stem cells
Phase image of embryoid bodies (EBs) formed from mouse embryonic stem cells  (Photo: Stemcellscientist [CC BY-SA 3.0] via Wikimedia Commons)

Stem cells, with their ability to form almost all the cells in the body, have remained a subject of intense scientific interest. In a recent study, a group of Indian scientists led by Deepa Subramanyam from the National Centre for Cell Science (NCCS) show that endocytosis, a process by which cells internalizes substances such as proteins, polysaccharides etc., is essential for stem cells to retain their stemness”.

Embryonic stem cells are a group of cells which reside deep within the mass of cells that are formed soon after fertilization of the egg during development. These cells have the remarkable ability to give rise to ~200 different cell types, based on the signals they receive from the outside environment. 

In the year 1981, Martin J Evans and Mathew Kaufmann from the University of Cambridge, UK, published a method to culture embryonic cell lines in the laboratory, which could then be artificially induced to differentiate into different cell types. This discovery brought the attention of the research community to the potential applications of embryonic stem cell technology, particularly in the fields of regenerative medicine and disease therapeutics. Since then the field has grown in leaps and bounds. 

While scientists all over the world are working on methods to transform stem cells into specific cell types, our knowledge on the pathways and molecules that help these stem cells to sustain their state of stemness” still remains scarce. In the present study, Subramanyam’s team add one piece to this puzzle by showing how endocytosis helps in maintaining the undifferentiated state of embryonic stem cells. 

In order to achieve proper and complete differentiation, it is critical to understand how certain factors can regulate the fate of stem cells,” says Subramanyam. The team knocked down the expression of Cltc, a protein required for endocytosis, in mouse embryonic cells and found that this reduces the ability of embryonic stem cells to stay in undifferentiated form. 

Deepa Subramanyam from the National Centre for Cell Science (NCCS)
Deepa Subramanyam’s team at the National Centre for Cell Science (NCCS)

Next, the scientists studied the effect of this loss of endocytosis on two molecules known to regulate the differentiation state of stem cells. They found that levels of E‑CAD, a protein that promotes maintenance of an undifferentiated state, decrease with the loss of endocytosis. On the other hand, expression of TGFβR1, a protein which drives differentiation of stem cells to different cell types, increases with the loss of endocytosis. This data suggests a mechanism for the link between endocytosis and maintenance of undifferentiated state of stem cells .

The report by Subramanyam’s group reconfirms and builds on the importance of the cellular transport machinery in actively regulating the stem cell state,” says Maneesha Inamdar, Professor at the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) who was not associated with the study. She added that the importance of studying transient interactions and the machinery that moves cargo into and within a cell has been becoming more and more evident over the years. 

Understanding how cellular processes such as endocytosis play a role in regulating the pluripotency of embryonic stem cells is important towards developing safer and more efficient cell-based therapies, ” says Subramanyam. 

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