Thursday, 2 April 2015

Stem Cells Age-discriminate Organelles to Maintain Stemness

Stem Cells Age-discriminate Organelles to Maintain Stemness
Thursday, 02 April 2015

Tissue stem cells, that continuously renew our tissues, can divide asymmetrically to produce two types of daughter cells. One will be the new stem cell, whereas the other will give rise to the differentiating cells of the tissue.

A study jointly leads by laboratories in the Institute of Biotechnology, University of Helsinki and Massachusetts Institute of Technology (MIT) investigated whether stem cells may also use asymmetric cell division to reduce accumulation of cellular damage. Damage build-up can cause stem cell exhaustion that result in reduced tissue renewal and aging.

Human mammary stem-like cell apportions
aged mitochondria asymmetrically between
daughter cells. Mitochondria were labelled age-
selectively red 51 hours prior to imaging, leaving
mitochondria that are younger unlabelled. The
daughter cell that will become the new stem cell
(bottom left) receives only few old mitochondria.
Credit: Julia Döhla. 
Researchers developed a novel approach to follow cellular components, such as organelles, age-selectively during cell division. Scientists in David Sabatini's lab studied stem-like cells (SLCs) from cultures of immortalized human mammary epithelial cells. These SLCs were chosen because they express genes associated with the stem-cell state (referred to as stemness), are able to form structures known as mammospheres in culture. To track the destinations of subcellular components during cell division, the researchers, led by former postdoctoral scientist Pekka Katajisto, tagged the components – including lysosomes, mitochondria, Golgi apparatus, ribosomes, and chromatin – with a fluorescent protein that glows when hit by a pulse of ultraviolet light.

"We found that stem cells segregate their old mitochondria to the daughter cell that will differentiate, whereas the new stem cell will receive only young mitochondria" says Pekka Katajisto, a Group leader and Academy research fellow at BI.

By tracing the movements of the glowing organelles, the researchers were able to demonstrate that while the normal epithelial cells distributed all of the tagged components symmetrically to daughter cells, the SLCs localized their older mitochondria distinctly and passed on the lion's share of them to the daughter cells headed for differentiation. The researchers ultimately found that the number of older mitochondria in those cells was roughly six times that in daughter cells whose fate was to remain as stem cells.

Mitochondria appear to be particularly important for stem cells, as other analysed organelles were not similarly age-discriminated, and since inhibition of normal mitochondrial quality control pathways stopped their age-selective segregation.

"There is a fitness advantage to renewing your mitochondria," says David Sabatini, Professor at MIT and Whitehead Institute.

"Stem cells know this and have figured out a way to discard their older components."

“While the mechanism used by stem cells to recognize the age of their mitochondria remains unknown, forced symmetric apportioning of aged mitochondria resulted in loss of stemness in all of the daughter cells," says Katajisto.

"This suggests that the age-selective apportioning of old and potentially damaged organelles may be a way to fight stem cell exhaustion and aging," says Katajisto who now runs a lab at the Institute of Biotechnology at University of Helsinki.

Katajisto laboratory is now exploring how old mitochondria differ from old, and whether this phenomenon occurs in other cell types beyond the human mammary stem-like cells examined here as well as in in vivo.

Contact: Pekka Katajisto

Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness 
Pekka Katajisto, Julia Döhla, Christine Chaffer, Nalle Pentinmikko, Nemanja Marjanovic, Sharif Iqbal, Roberto Zoncu, Walter Chen, Robert A. Weinberg, David M. Sabatini
Science April 2, .2015, DOI:10.1126/science.1260384

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