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Stem Cell Niche | Signaling pathways and Cell differentiation
#1
Stem cells with tumor cells are the only cells in human body that are able to proliferate and differentiate indefinitely. Self renewal is the key process in human organism because it has great importance in tissue homeostasis and regeneration. Surely, the promise of stem cells biology has given a hope for treatment of many diseases in regenerative medicine.
Homeostasis of human body is maintained by continuous stem cells division. By self-division and differentiation of daughter cells, stem cells are responsible for replacing of short-living and highly differentiated cells in skin, testicles and blood. Of course, this process must be strictly observed, because it can cause many dysfunctions in our body. Because of their importance, stem cells should be preserved as much as possible from damage or loss.

If little amount of cells differentiate, big number of cells can be created and it can lead to secondary mutation and tumor genesis. On the other way, if big amount of cells differentiate, the stem cell population may be reduced. However, critical decision between stem cell self-renewal and differentiation is controlled by microenvironment in which stem cells are located called stem cell niche. Stem cell niches provide support for stem cells and signalization (hormonal, neural and metabolic). Niches have been found in peripheral nervous system, skin, hair follicle, prostate, blood, breast, bone marrow and intestines. Many recent studies have begun to reveal different critical components of many stem cell niches. These critical components include various cell types like inflammatory, mesenchymal, glial, vascular and neuronal, then other factors like oxygen tension, temperature and matrix rigidity.

Interactions in the stem cell niche

There are several interactions in stem cell niche. Cell- cell interactions provide structural support, produce soluble signals that control function of the stem cell and have role in adhesion. Extra cellular matrix also has interactions with stem cells, and their interaction provides mechanical signals which allow stem cells to have adequate response to physical forces from the outside. Also, temperature, chemical signals and shear forces which are provided by the stem cell niche influence stem cell behavior.

Signaling pathways

Gene activated cascade of events dictate stem cell fate and function. These signaling pathways include Notch, Sonic Hedgehog, Wnt genes and BMI-1. Role of the Notch is very important in many stem cell niches, mainly in muscles, gut, mammary gland and hematopoietic system. This signaling pathway has role in stem cell division and it is activated when ligand and Notch receptor make connection. The Wnt genes has still blur image of their function, but they may have role in direct induction of stem cell self- renewal process, and possibly, they can influence stem cells in the niche. The BMI-1 signaling pathway has been found in neuronal stem cells and hematopoietic stem cells. The most possible function of BMI-1 signaling pathway is other somatic stem cells regulation of self- renewal. Sonic hedgehog signaling controls many growth aspects, and as many studies have shown, this signaling pathway controls stem cell- like cells in neocortex and proliferation of the cells in hippocampus and ventral forebrain.

Cell differentiation in stem cell niche

In stem cell niche, when stem cells receive signal, they begin division. This division can be asymmetric, bigger part stays in niche as stem cell, and another becomes a progenitor cell, leaves stem cell niche and continues differentiation. Also, division can be symmetric, and in this division type, both stem cells remain in niche. The key role of stem cell niche is adequate signaling system, which can tell stem cells to divide or not to divide. If niche doesn’t provide appropriate signal, stem cells begin to differentiate in short amount of time. Progenitor stem cells move away from the niche, and they are escorted by guardian cells.

If cell differentiation prevailed, the stem cell population within a niche would be decreased, and if self- renewal continued uncontrolled, the result would be quick tumor development. The role of niche is obvious, because niche provides necessary balance between differentiation and division. The niche environment is responsible for inhibition or induction of stem cell differentiation or division, based on the composition and size of stem cell niche. Surrounding tissue and extracellular matrix signals provide cell identity and commands their behavior. Functional cells arising from stem cells differentiate in intermediate- differentiated progenitor cells, that after a several divisions and differentiations, become differentiated cell, without ability to proliferate and that cell is treated as finally differentiated.

In every tissue, stem cells have high capacity for proliferation, but not every human stem cell divides with high frequency. Researchers have proven this by using fluorescent labeling to mark skin stem cells. These skin stem cells within the stem cell niche began to divide rapidly.
Stem cells have enormous potential in regenerative medicine in repairing diseased or damaged tissue because of their tumor initiation role. The stem cells niche have potential role in cancer treatment. These niches are maybe potential targets for radiation and chemotherapy treatments in order to destroy tumor stem cells. For example, mammary gland stem cells are controlled by reproductive organs as well as the niche to produce new tissues in order to create more complex way of stem cell self- renewal as well as chance for tumor progression. Similar to this is prostate tumor treatment. In prostate tumor, stem cell niche is in the basal layer, proximal to urethra, and this region has been identified as stem cell niche in the prostate gland.

Conclusion

Stem cells are fantastic and promising solution for regenerative medicine, but these cells are not only important in tissue renewal. As these cells must react very fast, they receive input information from their niche, which directs their destiny. When we understand complete interaction between stem cells and niche, we will dictate their activities to promote tissue regeneration. On the other hand, targeting these niches can help us in battle against many diseases such as tumors.
#2
Prostate cancer and stem cells

The original article in this thread outlines the features of stem cell niches throughout the body. As mentioned in the article, if self- renewal of stem cells continued uncontrolled, the result would be rapid tumour development. Many cancers contain cancer stem-like cell (CSC) subpopulations within the heterogeneous population of cells that make up a tumour. The original article in the thread mentioned the prostate as an example and pointed out that the prostate gland contains a stem cell niche in the basal layer, proximal to the urethra.

Many studies have linked disease progression, recurrence and treatment failures to the CSC subpopulation. Recent studies on prostate cancer have focused on this in an attempt to identify potential new therapeutic avenues. Different signalling intermediates and pathways have been the focus of these studies, for example the transcription factor Myc and the hedgehog pathway. Techniques such as RNA interference have been employed and delivery methods including nanoparticles explored.

For example, a study using RNA interference approaches with noncoding promoter-associated RNA (paRNA) focused on silencing transcription of transcription factor Myc, which has a central function in stem cell biology and in human cancers. Myc was silenced in CSC in cell culture and in xenograft models of human prostate cancer. The fraction of CSCs in the cell population was reduced, leading to reduced self-renewal, tumour initiation and metastases. Myc silencing altered the stem cell phenotype and induced senescence. Prostate tumour development was greatly reduced. Thus Myc was identified as a potential target in reducing the tumour initiation potential of CSCs, particularly via a RNA inhibition-based strategy.

The original article in this thread mentions the hedgehog signalling pathway, which has also been examined in recent studies to identify potential prostate cancer therapies. In this case, HPMA copolymer-cyclopamine conjugate was used a delivery system for cyclopamine, which blocks the hedgehog signalling pathway. Selectivity of this conjugate toward CSCs was confirmed in human prostate cancer epithelial cells, RC-92a/hTERT cells by measurement of stem cell marker expression and prostasphere culture and by observation of reduced CSC viability.

Dual functional nanoparticles were employed in another study which could be delivered in a targeted manner using a single-chain prostate CSC antigen antibody. The core of the nanoparticles contained poly(D,L-lactic-co-glycolic acid), docetaxel and superparamagnetic iron oxide nanocrystals (SPIONs) ) with a multilayer shell formed by poly(allylamine hydrochloride) and two different sized poly(ethylene glycol) molecules. Drug release profiles showed drug could be delivered in a controlled manner in vitro to PC3 cells, resulting in increased anti-tumour activity due to the release of the docetaxel and SPIONs and enhanced magnetic resonance imaging. In vivo mouse studies on nude mice with PC3M xenografts, the nanoparticles stopped or even reversed tumour growth and increased the lifespan of the mice.

Thus there are many promising avenues of research for prostate cancer therapy but only the future will tell how applicable these methods will be in human cancer.

Sources

CIVENNI, G. et al., 2013. RNAi-mediated silencing of Myc transcription inhibits stem-like cell maintenance and tumorigenicity in prostate cancer. Cancer research,

GAO, X. et al., 2012. Prostate stem cell antigen-targeted nanoparticles with dual functional properties: in vivo imaging and cancer chemotherapy. International Journal Of Nanomedicine, 7, pp. 4037-4051

ZHOU, Y., YANG, J. and KOPECEK, J., 2012. Selective inhibitory effect of HPMA copolymer-cyclopamine conjugate on prostate cancer stem cells. Biomaterials, 33(6), pp. 1863-1872
  

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Stem Cell Niche | Signaling pathways and Cell differentiation00