Biomedical Engineering Reference
In-Depth Information
6.6
Stem cell niche
Recently, it has been realized that stem cells exist in various adult tissues, not
just in constitutively renewing organs. The concept of stem cell niches
containing adult stem cells was first introduced by Schofield in the end of 1970
and refers to a subset of tissue cells such as fibroblasts, adipocytes, osteoblasts
and endothelial cells and their extracellular substrates, which in vivo regulates
stem cell fate.
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These niches are believed to be present across many species,
from the primitive Drosophila to humans. They are composed of not only the
stem cells themselves but also of a framework of other cell types within a rich
dynamic microenvironment that allows these cells to maintain their unique
intrinsic abilities of self-renewal and differentiation.
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The complex regulatory
mechanisms governing stem cell fate must be able to maintain a balance
between a self-renewal phenotype and that of a differentiated specialized cell.
This involves many signal transduction pathways, not yet well defined. A
detailed comprehensive coverage of this topic can be found in a recent review by
Fuchs et al.
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6.6.1 Molecular regulation of stem cell fate
Several mechanisms, both temporal and spatial, have been demonstrated to play
key roles in the regulation of a stem cell fate. It is now believed that extrinsic
control of stem cell fate relies on highly conserved signaling pathways
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that
interact with each other and include Wingless (Wnt), Notch/Delta, transforming
growth factor-/bone morphogenic protein (BMP-2), cyclin-dependent kinase
inhibitor p21, proto-oncogene Bmi-1, transcription factor HoxB4, JAK/STAT,
Rho and Sonic Hedgehog pathways.
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Furthermore, it has been suggested
that inputs from distinct signaling pathways must be integrated by the stem cell
in order to produce discrete biological output.
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For instance, Wnt signaling pathway was shown to play an active role not
only in multiple processes in animal development, but also as a major regulator
in the maintenance and self-renewal of HSC.
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Briefly, after binding to its
receptor, GSK-3-mediated phosphorylation of -catenin is inhibited, which
subsequently leads to the interaction of catenin with members of the LEF-1/TCF
family of transcription factors, thus activating expression of target genes
previously implicated in HSC renewal such as HoxB4 and Notch1. Furthermore,
Duncan et al. have recently shown how Notch signaling is critical for the
maintenance of an undifferentiated state by HSC and may hence act as a `gate-
keeper' between self-renewal and differentiation.
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This mechanism might
actually be activated by the Wnt pathway, highlighting once more the
integration of several pathways within a stem cell.
In addition to the signal identity, signal strength, which can be achieved by
altering either receptor or ligand concentration, has also been shown to have an
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