Abstract
Representing a renewable source for cell replacement, neural stem cells have received substantial attention in recent years. The neurosphere assay represents a method to detect the presence of neural stem cells, however owing to a deficiency of specific and definitive markers to identify them, their quantification and the rate they expand is still indefinite. Here we propose a mathematical interpretation of the neurosphere assay allowing actual measurement of neural stem cell symmetric division frequency. The algorithm of the modeling demonstrates a direct correlation between the overall cell fold expansion over time measured in the sphere assay and the rate stem cells expand via symmetric division. The model offers a methodology to evaluate specifically the effect of diseases and treatments on neural stem cell activity and function. Not only providing new insights in the evaluation of the kinetic features of neural stem cells, our modeling further contemplates cancer biology as cancer stem-like cells have been suggested to maintain tumor growth as somatic stem cells maintain tissue homeostasis. Indeed, tumor stem cell's resistance to therapy makes these cells a necessary target for effective treatment. The neurosphere assay mathematical model presented here allows the assessment of the rate malignant stem-like cells expand via symmetric division and the evaluation of the effects of therapeutics on the self-renewal and proliferative activity of this clinically relevant population that drive tumor growth and recurrence.
Highlights
Stem cells were thought to be located only in tissues where differentiated cells were most susceptible to loss and the need for replacement great, such as the skin [1], intestinal epithelia [2] and the blood [3]
(Figure 1b) If we keep the number of long-term proliferating (LTP) cells in a sphere constant and with each iteration change the total cells generated per sphere from 1000 (i) to 2000 (ii) to 4000 (iii), we find that the elevation of the growth curve is affected but not its slope
We previously demonstrated that 95% of the spheres in the neurosphere assay (NSA) cannot be passed more than 4 or 6 times suggesting the majority of the spheres are derived from short-term proliferating (STP) cells and that LTP cells exhibit a higher proliferative potential [20,21]
Summary
Stem cells were thought to be located only in tissues where differentiated cells were most susceptible to loss and the need for replacement great, such as the skin [1], intestinal epithelia [2] and the blood [3]. Adult stem cells represent a relatively quiescent reservoir of uncommitted cells These cells have the ability to divide throughout the lifespan of the organism to give rise to more committed progenitor cells generating a large number of undifferentiated cells. These progenitors differentiate into lineage-restricted functional cells. Due to their ability to give rise to new cells, the factors regulating the division of stem and progenitor cells, and the differentiation of their progeny is of great interest in treating CNS disorders resulting from the loss or inappropriate functioning of cells. While employing a functional read-out has made it possible to identify the presence (or absence) of stem cells in a population, it prohibits the direct isolation or discrimination of stem cells from non-stem cells thereby precluding any meaningful quantitative data pertaining to their frequency and/or expansion rate
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