If you’re a frequent reader of Signals, you’ve probably seen the phrase “self-renewal” at least once. And if you’re anything like me, you’re probably still a bit confused as to what it means. Yes, I admit it, even after being a part of the cancer stem cell field for over six years, I can still get confused about self-renewal.
Most cells in the human body need to divide to maintain the status quo (e.g. intestinal cells dividing to preserve the absorptive layer of our gut), or to complete a particular task (e.g. white blood cells dividing to fight an infection). These kinds of cells, with their designated functions, are considered terminally differentiated: they cannot become any other type of cell, or have any other function than what they are programmed to do. In order to ‘reproduce,’ these cells will divide to produce two identical copies of themselves, referred to as daughter cells (see figure, left side).
Eventually, these terminally differentiated cells get to a point where they can no longer divide. Without a supply of ‘fresh’ cells, some tissues in our body wouldn’t be able to last very long. This is where stem cells come in: they are able to provide a fresh source of the cells needed for bodily functions, for the lifetime of an organism, while maintaining the stem cell population.
This is accomplished through self-renewal, a process of cell division unique to stem cells. A stem cell will divide asymmetrically into two different daughter cells (see figure, right side). The first is an identical daughter cell, capable of maintaining the stem cell line. The second daughter is a more differentiated cell – a progenitor – that will be able to produce the terminally differentiated cells, but lacks the stem cell ability to replenish its own population.
So how does a stem cell know to divide into two different cells? From studies performed in fruit flies, stem cell researchers have observed two potential mechanisms for the asymmetrical cell division of stem cells.
The first is an intrinsic mechanism. When a cell divides, DNA is not the only thing that is passed on. All kinds of different proteins, essential to the survival and function of the cell, are also distributed between the two daughter cells. Typically, proteins are distributed equally among the daughter cells. However, researchers have observed that certain proteins, found to be regulators of self-renewal, are not distributed equally among the daughter cells.
During a cell division, these self-renewal regulators are aligned in a way that causes them to become part of only one daughter cell (the stem cell). While one daughter cell continues to possess the ability to self-renew, the other (and all its future daughters) have lost these regulating proteins; thus the ability to self-renew.
The second mechanism is considered to be extrinsic, whereby the surrounding microenvironment plays a role. In this mechanism, the surrounding microenvironment is responsible for providing signals necessary for stimulating self-renewal. The dividing cell is oriented such that one side (destined to become one daughter cell) is in closer proximity to the cells of the microenvironment. This daughter cell then receives the microenvironment’s signals to stimulate self-renewal properties, allowing it to maintain the stem cell population. The other daughter cell, without the supporting signals, becomes a more differentiated cell type.
As if self-renewal wasn’t already confusing enough – now there’s these mechanisms to think about too!
The last thing I want to mention about self-renewal is that stem cells don’t actually divide that often (in adults anyway – developing embryos are a different story). Since a stem cell produces a progenitor cell that does most of the heavy lifting, in terms of producing the cells needed by the body, it doesn’t have to divide that often.
As I mentioned in my previous post about cancer stem cell therapies, this is an important consideration for cancer treatment efficacy. Cancer stem cells, because they have the ability to self-renew, divide less frequently, and are protected from current therapies designed to disrupt cell divisions. Just like a stem cell, supplying fresh cells for the body, a cancer stem cell could supply fresh tumour cells, leading to disease relapse. Preventing self-renewal by targeting the mechanisms of asymmetric cell division is becoming of increasing interest for cancer stem cell researchers in an effort to prevent this small population of cells from repopulating the tumour (see, there is a method to all this self-renewal madness!).
Sara M. Nolte
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