IMAGE:Human mammary stem-like cell apportions aged mitochondria asymmetrically between daughter cells. Mitochondria were labeled age-selectively red 51 hours prior to imaging, leaving mitochondria that are younger unlabelled. The daughter cell... view more

Credit: Julia Dhla

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, where as the other will give rise to the differentiating cells of the tissue.

A study jointly lead by laboratories in the Institute of Biotechnology and Massachusetts Institute of Technology (MIT) investigated whether stem cells may also use asymmetric cell division to reduce accumulation of cellular damage. Damage buildup can cause stem cell exhaustion that results in reduced tissue renewal and aging.

Researchers developed a novel approach to follow cellular components, such as organelles, age-selectively during cell division.

"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.

Mitochondria appear to be particularly important for stem cells, as other analyzed 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. "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.

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.

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Stem cells age-discriminate organelles to maintain stemness

CAMBRIDGE, Mass. (April 2, 2015) - A team of Whitehead Institute scientists has discovered that during division, stem cells distinguish between old and young mitochondria and allocate them disproportionately between daughter cells. As a result, the daughter cell destined to remain a stem cell receives predominantly young mitochondria, while the cell meant to differentiate into another cell type carries with it a higher compliment of the aged organelles.

This asymmetric apportioning of cellular contents may represent a mechanism through which stem cells prevent the accumulation of damage in their lineage over time.

"There is a fitness advantage to renewing your mitochondria," says Whitehead Member David Sabatini, whose lab reports on the phenomenon online this week in the journal Science. "Stem cells know this and have figured out a way to discard their older components."

Among the hallmarks of stem cells is so-called asymmetric cell division. Unlike their ordinary cellular counterparts, which divide symmetrically to create two cells with identical fates, stem cell division can produce one daughter cell that will remain a stem cell and another bound for further differentiation into another cell type. Scientists have observed that non-mammalian organisms are able to apportion damaged components asymmetrically during cell division, but it was unclear whether mammalian stem cells could behave similarly.

To answer this question, scientists in 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.

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.

In a series of additional experiments, the scientists found that cells that inherited fewer old mitochondria during asymmetric division formed three times the number of mammospheres per 1000 cells than the daughter cells inheriting a greater proportion old mitochondria. This was an indication that cells with fewer of these old organelles were, by the mammosphere-forming criterion, more stem-like. Further, they discovered that chemically disrupting the cells' inherent mitochondrial quality-control mechanisms prevented asymmetric apportioning of young and old mitochondria and caused the loss of stem-like characteristics. Taken together, these results indicate that this disproportionate allocation of aged mitochondria during stem cell division is essential for maintaining stemness in the next generation.

"While we do not know how stem cells recognize the age of their mitochondria, forced symmetric apportioning of aged mitochondria resulted in loss of stemness in all of the daughter cells," says Katajisto, the first author of the Science paper who now runs a lab at the Institute of Biotechnology at University of Helsinki. "This suggests that the age-selective apportioning of old and potentially damaged organelles may be a way to fight stem cell exhaustion and aging."

Katajisto is now exploring whether this phenomenon occurs in other cell types beyond the human mammary epithelial SLCs examined here as well as in in vivo studies.

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Age-discrimination during cell division maintains the 'stem' in stem cells

According to the Christopher and Dana Reeve Foundation, nearly one in 50 people are living with paralysis.

Until now, there wasn't much hope.

But, a new study involving stem cells has doctors and patients excited.

Two years ago, Brenda Guerra's life changed forever.

"They told me that I went into a ditch and was ejected out of the vehicle," says Brenda.

The accident left the 26-year-old paralyzed from the waist down and confined to a wheelchair.

"I don't feel any of my lower body at all," says Brenda.

Brenda has traveled from Kansas to UC San Diego to be the first patient to participate in a ground-breaking safety trial, testing stem cells for paralysis.

"We are directly injecting the stem cells into the spine," says Dr. Joseph Ciacci, a neurosurgeon at UC San Diego.

The stem cells come from fetal spinal cords. The idea is when they're transplanted they will develop into new neurons and bridge the gap created by the injury by replacing severed or lost nerve connections. They did that in animals and doctors are hoping for similar results in humans. The ultimate goal: to help people like Brenda walk again.

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Stem cell procedures for paralysis patients