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Unexpected influence on how stem cells divide

Most cells divide by simple division into 2 identical cells, mitosis. But, stem cells have options. They can regenerate themselves through mitotic division or differentiate one daughter cell into virtually any specialized cell. However, this only can happen if mini-organs peroxisomes are distributed evenly throughout the stem cell.


Reporting February 3 in Science magazine, researchers at Rockefeller University discovered that a stem cell's pivotal decision making appears to hinge on whether or not tiny organ-like structures, called peroxisomes, are dispersed equally within that stem cell.

The researchers focused on PEX11b, a protein associated with peroxisomes, organelles which are involved in fatty acid and energy metabolism within cells. A deficiency of PEX11b compromised the differentiation and subsequent barrier formation within cells. Without PEX11b, peroxisomes functioned but failed to localize or segregate properly during mitosis.

"In order for the body's tissues to develop properly and maintain themselves, renewal and differentiation must be carefully balanced," says senior author Elaine Fuchs PhD, the Rebecca C. Lancefield Professor and head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development. "Our experiments suggest an unexpected role for the positioning and inheritance of cellular organelles, in this case enzyme-filled peroxisomes, in controlling this intricate balance."

The outer section of our skin, the epidermis, provides a protective barrier for the body, and stem cells reside deep within it.  First author Amma Asare, a graduate student in the lab, wanted to know how skin cells first emerge and begin their transition.


During development, stem cells divide so that one stem cell daughter remains inward while the other daughter cell differentiates and moves outward to become part of the outer layers of skin (epidermis).


Looking at developing mouse skin, Asare devised an approach to identify genes that help guide the balance between the stem cell dividing into one new cell that remains stem-like and another new cell differentiating into a specialized cell type. One particular protein — Pex11b — caught her attention. Pex11b is associated with the membrane that surrounds a peroxisome. A peroxisome is a tiny organelle in a cell's cytoplasm that contains the enzyme catalayse, and some oxidases. These enzymes reduce long fatty acids into medium chain fatty acids, that are then shuttled into mitochondria, the "batteries" of a cell. Inside the mitochondria, fatty acid chains are broken down into carbon dioxide and water.


Asare found that the Pex11b protein appears to ensure peroxisome organelles stay in the right position to keep the spindle perpendicular to the basement membrane. This allows for a balanced division — mitosis —between the two daughter cells.

In cells that lack Pex11b, peroxisomes weren't evenly divided — and in some cases, one daughter cell ended up with all of the peroxisomes and the other none.

In those cells whose peroxisome distribution was disrupted, cell division took longer, as the mitotic spindle separating daughter cells' genetic material didn't align correctly.


Asare found the result of depleting skin stem cells of Pex11b was that fewer daughter cells were able to differentiate into mature skin cells.

Researchers next moved peroxisomes around in the cell using a sophisticated laboratory technique, but the effect was the same. The affect on the whole organism was dramatic. If peroxisome positions were disrupted in stem cells, mice embryos could no longer form normal skin.


"If peroxisomes are in the wrong positions during cell division, no matter how they got there, that slows down the process."

Amma Asare, graduate student under Elaine Fuch, Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA


"While some evidence already suggested the distribution of organelles, including energy-producing mitochondria, can influence the outcome of cell division, we have shown for the first time that this phenomenon is essential to the proper behavior of stem cells and formation of the tissue," says Fuchs, who is also a Howard Hughes Medical Institute Investigator.

Abstract
Peroxisome inheritance and differentiation
For normal tissue structure and function, cells exert strict control over growth versus differentiation. Poor wound healing and aging can result from too little proliferation. Conversely, the development of cancer can involve excessive cell growth. Asare et al. looked for regulators that balance proliferation and differentiation in the epidermis (see the Perspective by Gruneberg and Barr). They observed differences in the transcript profile of epidermal progenitors, their differentiating progeny, and epidermal cancers. Epidermal progenitors that were deficient in the peroxisome-associate protein Pex11b did not segregate peroxisomes properly among dividing cells. This led to a delay in mitosis that perturbed polarized divisions. These events skewed daughter cell fate and resulted in a defective skin barrier. Thus, peroxisome inheritance appears to play a role in normal mitosis and cell differentiation.

Science, this issue 10.1126/science.aah4701; see also p. 459
Structured Abstract

INTRODUCTION
Adult tissues must balance growth and differentiation to develop and maintain homeostasis. Excessive differentiation can lead to aging and poor wound healing. Too much growth is observed in hyperproliferative disorders and cancers. How tissue imbalances arise in disease states is poorly understood.

Skin is an excellent system for understanding the importance of this balance. Essential for keeping harmful microbes out and retaining body fluids, the skin barrier is maintained by an inner layer of proliferative basal progenitors, which generate a constant outward flux of terminally differentiating cells. It is known that when epidermal progenitors accumulate mutations that will give rise to malignancy, they change their program of gene expression. However, the extent to which cancer progression involves a gain of proliferation versus a loss of differentiation is unclear. A detailed molecular knowledge of how normal basal epidermal progenitors transition from a proliferative, undifferentiated state to a terminally differentiated state allows us to investigate how this process goes awry in a tumorigenic state. We use a genetic screen to identify which of the gene changes that occur in both early cell commitment and cancer are integral to maintaining the balance between growth and differentiation
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Feb 24, 2017   Fetal Timeline   Maternal Timeline   News   News Archive

Above a dividing cell, reveals tiny (GREEN) organs called peroxisomes evenly distributed
in distinctive arcs. In cells without the protein Pex11b, peroxisomes do not distribute equally.
Image Credit: Laboratory of Mammalian Cell Biology and
Development at The Rockefeller University/Science  

 

Phospholid by Wikipedia