Abstract: Stem cell niches are found in specialized sites located in adult tissues and are regulated by extrinsic

and intrinsic factors. Stem cell niches are responsible for the maintenance of stem cells that are unique to that specific niche. These niches have their own distinct morphology in terms of their location in the body and the cells involved in maintenance of the niche. Stem cells and their niches will be further discussed through a look at the hematopoietic stem cell niche and its morphology and function. Ncadherin is a protein that is involved with the HSC niche and is thought to be crucial in the mediation of cell-cell adhesion in this particular niche. Primary research articles will be discussed to further explore the role of this protein in the HSC niche.

Introduction: Stem cells are undifferentiated cells that can be self-renewed even after long periods of dormancy and can also be induced to become specialized cells. Stem cells can be divided into two distinct categories: 1) embryonic stem cells (ESCs) and 2) adult/somatic stem cells (ASCs). The main difference between these two stem cell types is that ESCs are capable of self-renewing in culture without differentiating for a year or more and ASCs cannot. Another major differences between ESCs and ASCs is that ESCs are pluripotent and ASCs are multipotent. This means ESCs can give rise to many different tissue/cell types whereas ASCs are only capable of differentiating into a few different cell types. A stem cell niche is a microenvironment that maintains stem cell identity through a variety of intrinsic or extrinsic factors. These niches are sustained by supporting cells that provide the necessary signals for the maintenance of stem cells and the differentiation of stem cells into their specific cells types. An example of a stem cell niche includes the hematopoietic stem cell niche located in the bone marrow. The role of this niche is to renew HSCs and either maintain them as stem cells in the bone cavity or induce differentiation into a specific blood cell which is then released into the blood stream. Hematopoietic stem cells give rise to all types of blood cells including, red blood cells, B-lymphocytes, T lymphocytes, natural killer cells, neutrophils, basophils, eosinophils, monocytes, and macrophages. The osteoblastic and vascular niches are the two niches that support HSCs (Figure 1: Brief overview of hematopoeisis). (The National Institutes of Health resource for stem cell research, 2001).

Niche Morphology: Osteoblasts and endothelial cells are two types of cells that have been identified as part of the HSC niche. Osteoblasts can be found in a layer along the endosteum, which is a vascular membrane along the endosteal bone surface. The notion that osteoblasts may be involved in the regulation of HSCs is supported by research that suggests that angiopoietin-1, a product of osteoblasts, is a positive regulator of HSCs (Arai et al. 2004). Further support is provided by a study in which it was discovered that an increase in spindle-shaped N-cadherin osteoblastic (SNO) cells correlated with an increase in HSCs in mice models (Zhang et. al 2003). In the osteoblastic niche model of the HSC niche it is suggested that adhesive interactions between osteoblasts and HSCs are required for HSC maintenance. Endothelial cells are cells that comprise the lining of all blood vessels in the human body. The junctions between vascular endothelial cells are the sites at which movement of blood cells between the blood stream and bone marrow is mediated. Endothelial cells are important regulators in the mobilization of HSCs into the blood stream where they can undergo apoptosis and thus, provide a method of regulation, which helps maintain the number of HSCs in the niche (Yin et al. 2006). The theory endothelial niche is supported by research that suggests HSCs and endothelial cells are derived from the same progenitor cells hematopoiesis and vascularization occur simultaneously during embryonic development. It has also been suggested that both niches work together while the osteoblastic niche provides a quiescent microenvironment and the vascular niche promotes proliferation and further differentiation. Hematopoietic stem cells are found in the bone marrow next to the endosteal surface of the bone. The endosteal surface refers to the inner surface of the hard bone matter that encases the bone marrow. In culture, hematopoietic stem cells morphologically look and behave like white blood cells. Studies have shown that long-term progenitor cells and short-term progenitor cells are the two types of hematopoietic stem cells that exist. It was discovered in a 2006 study by Harrison et al., that in mice, long-term blood progenitor cells were capable of renewing themselves over the lifetime of the organism. On the other hand, short-term blood progenitor cells were only capable of renewing themselves for three to four months. (Morphology of the HSC niche: Figure 1)

Figure 1: The fate of the HSC and the morphology of the HSC niche in human bone (Yin T., and Li L L. (2006). The stem cell niches in bone. The Journal of Clinical Investigation. 116(5): 1195 : 11951201.)

Cadherin The Role of N-Cadherin in the HSC Niche: Cadherins are a group of cell adhesion molecules that are known to be significantly involved in embryonic development. N-cadherin is a class of cadherin protein that is commonly expressed on cadherin neural, endothelial, and muscle cell surfaces. In studies by Gordon, (1988) Petrides and Dittmann, 88) (1990) it was discovered that cell adhesion molecules played an important role in regulating the release of developing blood cells from the bone marrow and into the blood stream. In a study published in the Paper of Cell Science in 2001 researchers Puch et al. found that N-cadherin is also expressed on the cadherin surface of stromal cells in the bone marrow. This study also showed that N-cadherin is also expressed cadherin on a population of early hematopoietic progenitor cells in culture. Puch et al. used an anti anti-cadherin anti body and found that their attempts to inhibit bone marrow stromal cell-hematopoietic progenitor cell hematopoietic interactions using this anti-body were unsuccessful However, they suggested that other adhesion body unsuccessful. molecules may also play a role and the involv involvement of N-cadherin should not be ruled out. Another part cadherin of this study included the use of the anti anti-N-cadherin anti-body on developing blood cells and the results demonstrated an inhibition of cell aggregation between the developing blood cells. T researchers The concluded that N-cadherin could be accountable for cell-cell interactions between early progenitor cells cadherin cell that share the same differentiation sta It was also discovered that although, colonies were able to form state.

from single progenitor cells without cell-cell adhesion the anti-N-cadherin anti-body still inhibited colony formation. This result suggested two ideas: 1) N-cadherin could act as a signal-transducing molecule in addition to its function as a cell adhesion molecule ; and 2) the antibody could not serve as a replacement for the activating ligand. The osteoblastic niche model suggests that HSCs are maintained through adhesion to Osteoblasts via N-cadherin. However, in a more recent study it was discovered that hematopoietic stem cells do not depend on N-cadherin to regulate maintenance of HSCs (Kiel et al. 2009). In this study, the researchers could not detect the expression of N-cadherin on the cell surface of HSCs. The Kiel et al. lab also successfully genetically deleted N-cadherin from the HSC surface and discovered that hematopoiesis and HSC frequency and function was unaffected in mice that were Ncadherin deficient.

Conclusion: In conclusion, although the number of conclusive studies on the role of N-cadherin is minimal it is generally shown that N-cadherin mediates the adhesion of ell-cell interaction in early progenitor cells. Experiments in this study also indicate that the role of N-cadherin may not be limited to mediation of cell adhesion. Results imply that N-cadherin may also play a role in signal transduction between cells. However, N-cadherin is not involved in HSC to osteoblast adhesion and genetic deletion of N-cadherin had no effect on hematopoeisis or on the function of HSCs and their niche. Therefore, it can be said that the exact role of N-cadherin in the maintenance of the HSC niche is yet unclear.

Works Cited Arai, F. Hirao, A. Ohmura, M. Sato, H. Matsuoka, S. Takubo, K. Ito, K. Koh, G.Y. Suda, T. (2004). Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149161.10.1016/j.cell.2004.07.004 Chen, J., Astle, C.M., and Harrison, D.E. (1999). Development and aging of primitive hematopoietic stem cells in BALB/cBy mice. Exp. Hematol. 27, 928935. Gordon, M. Y. (1988). Adhesive properties of haematopoietic stem cells. Br. J. Haematol. 68, 49-151. Kiel M., Acar M., Radice G., Morrison S., (2009). Hematopoietic stem cells do not depend on Ncadherin to regulate their maintenance. Cell Stem Cell. 4(2): 170179. The National Institutes of Health resource for stem cell research. (June 17th, 2001). Hematopoietic Stem Cells. Retrieved November 10th, 2009 from, http://stemcells.nih.gov/info/2001report/chapter5.asp Petrides, P. E. and Dittmann, K. H. (1990). How do normal and leukemic white blood cells egress from the bone marrow? Blut 61, 3-13. Puch et al. (2001). N-cadherin is developmentally regulated and functionally involved in early hematopoietic cell differentiation. Journal of Cell Science. Yin T., and Li L. (2006). The stem cell niches in bone. The Journal of Clinical Investigation. 116(5): 11951201. Zhang, J. Niu, C. Ye, L. Huang, H. He, X. Tong, W.G. Ross, J. Haug, J. Johnson, T. Feng, J.Q. (2003). Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425,