Geometry of the stem cell’s micro-environment can influence organ aging and susceptibility to cancer.

Stem cells are the raw materials of the body, the cells that give rise to all other cells with specific tasks. Stem cells divide to create new cells in the body or in a laboratory under the correct conditions. Referred to as daughter cells, these cells either become new stem cells (self-renewal) or specialized cells (differentiation), such as blood cells, brain cells, heart muscle cells, or bone cells. No other cell in the body has the potential to naturally create new cell types.

A stem-cell niche is a tissue region that provides a specific microenvironment for stem cells that are undifferentiated and self-renewable. The stem-cell niche interacts with stem cells in order to keep them alive or to encourage their development.

Because a cell’s decision to differentiate or remain a stem cell is influenced by its local cellular and chemical environment, tissue architecture is predicted to have a role in cell proliferation dynamics. The research from University of California at San Diego introduces a theoretical model designed to measure the niche proliferative potential, and how the shape of the stem cell niche is influencing its proliferative potential and susceptibility to cancer.

The geometry of the stem cell niche is expected to play a role in determining the stem cell division sequence and differentiation. A smaller surface-to-volume ratio is associated with higher susceptibility to cancer, higher tissue renewal capacity, and decreased aging rate, said Blagoev.

Different stem cell niche architectures are shown. In A, a disconnected stem cell niche is shown. Blue cells correspond to stem cells and red to progenitor cells. Orange cells are more differentiated than red cells. B shows a one-dimensional niche; C and D correspond to different arrangements in two-dimensional niches. Different blue colors indicate the different stem cell “layers” niche. © Krastan B. Blagoev

To offer tissue maintenance and repair in various organs, stem cells must maintain their niche by self-replication while also maintaining the organ in which they reside by generating differentiated cells. Both functions are achieved by adult-tissue stem cells’ capacity to generate daughter cells. The homeostatic requirement that stem cell numbers remain roughly constant is a significant constraint on their growth.

Progenitor cells divide only a few times until they become fully committed differentiated cells with no renewal capacity. In fast renewing tissues like the skin, intestines, and hair follicles, stem cells have to go through many cell divisions during the life of the organism, but the possible number of stem cell divisions is limited by the gradual erosion of their chromosome ends containing telomeric DNA.

Telomeres are DNA–protein complexes that protect the ends of linear chromosomes from the DNA repair machinery and chromosome fusion. At each cell division, part of each telomere is lost, and cells lacking a mechanism to counter this loss gradually reach a point at which the cell cycle stops.

This loss in telomeres eventually leads to organ depletion of proliferative stem cells, reducing the regenerative abilities of the tissue. Although contributing to aging, proliferative slowing in aging organisms also serves as a cancer-protective mechanism by limiting the number of mutations that a cell can acquire as well as protecting cells with critically short telomeres from chromosome instability.

To counter the telomere erosion process, the geometric model proposed in the paper depends on the pattern of stem cell divisions determined by their sequence of symmetric and asymmetric divisions. Assuming that the decisions made by a stem cell to divide and the decision of its daughter cells to remain stem or to differentiate are based only on the local environment, the research shows that the architecture of the stem cell niche may determine the tissue-maintaining potential of this niche.

Another finding is that stem cell niches with structure supporting larger tissue maintenance potential are associated with higher probability for the accumulation of mutations in a single cell, and thus stem cell niches with high proliferative capacity are more prone to cancer transformation compared to niches with lower proliferative capacity.

Three different modes of stem cell division. A stem cell (blue) can divide asymmetrically into a stem cell and a transit-amplifying (TA) cell (red), or symmetrically into two TA cells or two stem cells. © Krastan B. Blagoev
To maintain their stem cell niche, an approximately constant number of stem cells needs to be kept. For disconnected stem cell niches, stem cells divide independently as shown in A. Alternatively, in connected stem cell niches, the stem cells can maximize the number of symmetric stem cell divisions (B), which leads to practically infinite proliferative potential. © Krastan B. Blagoev
A single cell can replenish the niche. The telomere lengths of the resulting stem cells will depend on the exact order of stem cell divisions. Here the telomere lengths of the cells in the niche are shown and the corresponding cells possessing these telomeres are indicated in different colors. © Krastan B. Blagoev

By sensing their environment the stem cells will not divide when are surrounded only by stem cells. Thus, the geometry of the cell’s boundary will define the number and the type of divisions in a cell’s life. When a cell on the boundary reaches the end of its proliferative capacity and divides symmetrically into two differentiating cells, a stem cell from the interior divides symmetrically, repopulating the stem cell compartment, and the daughter cell on the boundary divides asymmetrically until it reaches the end of its proliferative capacity, and so on. This process can continue until the final stem cell generates two differentiating cells, at which point the corresponding tissue’s capacity to replenish and heal itself is terminated.

The increased probability of dividing cells acquiring mutations will result in a shorter time to cancer in compact niches. Given the same mutagenic stress, Krastan predicts that organs with compact niches will develop cancer earlier than organs with unconnected niches and shorter telomeres.

The tissue maintenance potential is increased when the chance of symmetric divisions is greater than the probability of cell division. The greater the growth, the longer the telomeres of the new stem cells.

It is possible that some cancers might proliferate in the absence of telomerase or ALT (alternative lengthening of telomeres). In the simulations presented here, the probabilities for symmetric stem cell division into two stem cells or two differentiated cells were chosen equal to balance the two processes. It is possible that, during carcinogenesis, the process of symmetric division into two stem cells acquires a higher probability and disrupts homeostasis in the niche.

The spatial and temporal distribution of biochemical gradients in the tissue may also impact the phenotypic variety and shape of the stem cell niche. Cancer cells have the ability to flip between phenotypes, although the significance of tumor architecture is yet unknown. Studies of genetic switches in cell populations show that the reaction of the switches is environment-dependent, but how different geometries impact this response has to be investigated further.

Organ aging and susceptibility to cancer may be related to the geometry of the stem cell niche, Krastan B. Blagoev

Published: November 2011
DOI: 10.1073/pnas.1106105108

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