Biomedical Engineering Reference
In-Depth Information
Mutations in the BMP receptor type Ia cause juvenile polyposis, an inherited
polyposis syndrome (see later) (Howe et al., 2001). Experiments in mice have
shown that Bmp receptor 1a mutations result in the expansion of epithelial
precursor cells that form new crypt-like precursor cell compartments in the zone
normally restricted to differentiated cells (He et al., 2004). An interaction
between BMP and Wnt signaling is suggested by the accumulation of cells
with nuclear b-catenin in these mice.
2.2.4 Hedgehog Signaling
Hedgehogs act through a complex receptor system. Hedgehogs bind the
transmembrane receptor Patched. In the absence of Hedgehog, Patched
restricts the activity of the signaling receptor Smoothened, probably through
the control of the cellular localization of a second messenger molecule
(Bijlsma et al., 2006). Upon binding of Patched by Hedgehog this negative
regulation of Smoothened is relieved and signaling through Gli transcription
factors ensues. The major Hedgehog in the colon is Indian Hedgehog (IHH).
IHH is produced by colonocytes at the top of the crypt and stimulates
differentiation of the enterocyte lineage (van den Brink, 2007). In addition,
IHH antagonizes Wnt signaling, and a gradient of IHH from the top to the
base of the crypt may be one of the factors that restrict active Wnt signaling to
the bottom of the crypt.
2.3 Clonal Stem Cell Expansion in Colonic Epithelial
Damage and Repair
Homeostasis of stem cell behavior is not only tightly regulated at the level of the
single homeostatic crypt. Somehow the colonic epithelium is able to sense the
number of stem cells present in a crypt or tissue zone encompassing several crypts
and allows temporary lateral clonal expansion of stem cells during postnatal
growth and in situations of damage (stem cell loss) and repair (stem cell replace-
ment) (Leedham and Wright, 2008). This tightly controlled process involves the
budding and subsequent fission of a single crypt to form two or more crypts from
a single stem cell in a clonal manner (Greaves et al., 2006). The classical example
of this manner of tissue regeneration is in inflammatory bowel disease where
crypt fissioning is used as a pathological hallmark of the chronicity of the disease.
A dramatic example of the impressive capacity for crypt renewal through lateral
stem cell expansion was provided by Muncan et al. (2006) in c-myc conditional
mutant mice. The strategy employed to conditionally knock-out c-myc resulted
in a virtually complete loss of c-myc from the small intestine. The c-myc knock-
out crypts became hypoplastic and retarded in growth. Somehow the few percent
of remaining c-myc-positive crypts were able to repopulate the entire small
intestine with c-myc-expressing crypts within 28 days. Unfortunately, the mole-
cular mechanisms that restrict clonal stem cell expansion through crypt fissioning
