Biomedical Engineering Reference
In-Depth Information
central nervous systems. In each case, stem cells are formed in normal numbers
during fetal development but exhibit impaired self-renewal and become depleted
postnatally. Bmi-1 promotes stem cell self-renewal partly by repressing p16Ink4a,
a cyclin-dependent kinase inhibitor, and p19Arf, a p53 agonist (
29,
31
) . Both of
these checkpoint proteins negatively regulate cell proliferation, and their
increased expression has been associated with cellular senescence. This demon-
strates that stem cells require mechanisms to prevent premature senescence in
order to self-renew throughout adult life. In contrast, restricted neural progenitors
from the enteric nervous system and forebrain proliferate normally in the absence
of Bmi-1. Thus, Bmi-1 dependence is conserved between stem cells and distin-
guishes the cell cycle regulation of stem cells from the cell cycle regulation of at
least some types of restricted progenitors. Using similar approaches, the addi-
tional pathways were studied that hypothetically will also regulate stem cell self-
renewal, and that will contribute to understanding the molecular basis for
self-renewal (
29
). Since stem cells persist throughout life by self-renewing in
numerous tissues including the central and peripheral nervous system, this raises
the issue of whether there is a conserved mechanism to effect self-renewing
divisions. Deficiency in the polycomb family transcriptional repressor
Bmi-1
leads to progressive postnatal growth retardation and neurological defects.
Weimanmn et al. have shown that
Bmi-1
is required for the self-renewal of stem
cells in the peripheral and central nervous systems but not for their survival or
differentiation (
31
). The reduced self-renewal of
Bmi-1-
de fi cient neural stem
cells leads to their postnatal depletion. In the absence of
Bmi-1,
the cyclin-dependent
kinase inhibitor gene
p16Ink4a
is upregulated in neural stem cells, reducing the
rate of proliferation. Deficiency of
p16Ink4a
partially reverses the self-renewal
defect in
Bmi-1−
/− neural stem cells (
29,
31
) . This conserved requirement for
Bmi-1
to promote self-renewal and to repress
p16Ink4a
expression suggests that
a common mechanism regulates the self-renewal and postnatal persistence of
diverse types of stem cell. Restricted neural progenitors from the gut and fore-
brain proliferate normally in the absence of
Bmi-1
. Thus,
Bmi-1
dependence dis-
tinguishes stem cell self-renewal from restricted progenitor proliferation in these
tissues. BM-1-deficient NSC exhibit a reduced rate of proliferation (
31
) . Cells
within
Bmi1−/−
stem cell colonies divide at a reduced rate, leading to reduced
colony size, a reduced rate of BrdU incorporation into cells, and reduced stem
cell self-renewal. Since
Bmi-1
is necessary for adult stem cells from the
hematopoietic and nervous systems to self-renew normally, the defects in its
expression or function might cause neurological problems.
Neurotropic Factors and Receptors
•
Endothelin receptor B (Ednrb)
Wild-type neural crest stem cells (NCSCs)
NCSCs are one variety of tissue or “adult” stem cells. NCSCs persist in
peripheral nerves throughout late gestation but their function is unknown (
32
) .
