Stem Cells and….Clocks

Stem Cells and….Clocks
by Anastasia Sideri
Biologist-Biochemist (PhD)


Stem cells are precursor cells found in all multicellular organisms. They are characterized by the ability both to renew, through cell division, and to differentiate into a diverse range of specialized cell types, which is, also, known as plasticity. The balance between self-renewal and differentiation is finely tuned, so that the stem cell population is maintained.
Stem cells are at the forefront of the rapidly evolving field of cellular therapy. The scientific developments in stem cell research contribute to our knowledge of how an organism develops from a single cell, and most importantly, how healthy cells may replace unhealthy or damaged cells. The medical field dealing with the replacement of damaged cells by healthy ones is called Regenerative or Reparative Medicine. Scientists are continuously discovering new, promising applications of stem cells that could prove revolutionary for the treatment of human disease in the future.
There are generally two broad types of stem cells:
•Embryonic stem cells: Derived from up to 5th-day fertilized eggs (blastocyst stage). Due to their origin, they are highly controversial and the subject of many bioethical debates in the media.
•Adult stem cells: Adult stem cells are isolated from newborns, children and adults.
There are adult stem cells throughout life in essentially all tissues of the human body, such as brain, bone marrow, liver, brain, heart, pancreas, retina as well as hair follicles, amnion and endometrium. There are differences amongst the stem cell populations that are specific to a tissue. Over time, these populations tend to decline in number, but their presence is important for restoration and/or regeneration of local tissue damage.
The most extensively studied adult stem cells are hematopoietic stem cells (HSCs) that differentiate to blood and immune system components:
 Red blood cells, which transfer oxygen to all other cells of the body.
 White blood cells, which contribute to immune system defense against infections.
 Platelets, which contribute to blood coagulation.
 All progenitor cells, which compose human blood.
Hematopoietic stem cells (HSCs) can be isolated from bone marrow and peripheral blood in adults and children, as well as, umbilical cord blood in newborns (the blood that remains between the umbilical cord and placenta following birth). There are currently many publications on the successful differentiation of HSCs in neural, pancreatic, myocardial, hepatic and other tissue cells, both under laboratory conditions (in vitro) and in humans (in vivo).
HSCs reside in a specific region in the bone marrow, also known as stem cell niche, and only a minor percentage circulates in the peripheral blood under steady-state conditions. Following medical treatment with mobilization drugs, however, the stem cells can be forced from their niche in the peripheral blood. They can, then, be harvested from the blood, via a process that is less invasive and painful, compared to their isolation from the bone marrow.
It was recently found that release of HSCs from the bone marrow is regulated by a highly conserved, across species, set of genes encoding the “core circadian regulatory proteins” (CCRP). The CCRP act as molecular biological clocks to direct the oscillatory circadian (rhythmic) expression of genes that are essential for key metabolic events. CCRP expression is affected by light:dark cycle changes, feeding and physical activity pattern. Stem cell release from the bone marrow undergoes circadian oscillations in humans, emerging from the bone marrow into the bloodstream at higher concentrations at night than in the day. The opposite applies to mouse HSCs, since the mouse’s time of rest is daytime. Circadian oscillations have, also, been observed in bone marrow stem cells in vitro, by interfering with their growth conditions. Scientists verified that these physiological cycles are maintained during treatment of patients with mobilization drugs, too. The number of stem cells they were extracted from cancer patients who underwent the mobilization procedure before 12:30 pm was lower compared to that of patients who underwent the procedure before 3:30 pm. Circadian oscillations have been observed in adult stem cells other than hematopoietic, too.
The physiological significance of this observation is not fully elucidated. Biologists have observed that cell division in normal cells in species ranging from unicellular organisms to humans peaks at specific times of the day and consider this as indirect evidence that the process is regulated by their internal biological clocks. Cells in the human mouth, for example, tend to divide in the evening, just before nightfall. This could be explained evolutionary in the sense that ultraviolet light is one of the primary causes of mutations. Since cells are particularly vulnerable to mutations during cell division, cells that divide at night confer a selective advantage to the organism. It is, therefore, not surprising that the malfunction of biological clocks, in such a way that there is no control in cell division, is, also, implicated in the transformation of healthy stem cells to cancerous, since there is growing amount of evidence suggesting that cancer-initiating cells are indeed malfunctioning stem cells. The circadian, neutrally-driven release of HSCs during the resting period may promote the regeneration of the stem cell niche and possibly other tissues.
HSCs are commonly used to replenish a patient's stem cells, which are depleted during cancer therapy. Interfering with circadian oscillation could be valuable in clinical practice, since stem cells are currently harvested during the day. A simple change in hospital procedures to collect the stem cells in the afternoon or evening could, therefore, significantly increase the stem cell yield that is available for therapy. The biological clock pathway could be an effective target for anti-cancer drug development, by restoring the control of the biological clock over cell division.