X-Message-Number: 27930
Date: Sat, 13 May 2006 08:29:23 -0700 (PDT)
From: Doug Skrecky <>
Subject: aging of the stem cell niche

[A number of arguments could be marshalled that the main driving
force behind aging is a reduction in the size of the stem cell
niches. With fewer stem cells to replenish cells that die from
apoptosis or necrosis, brains become progressively more vulnerable to
dementia, muscles shrink, and arteries become much more vulnerable to
atherosclerosis. Hormone treatment can help to temporarily "rejuvenate" by
increasing stem cell proliferation on a short term basis, but eventually
this increased proliferation seems only to help further age the stem cell
niche. Senescent stem cells physically filling these limited niches is an
interesting theory for why this comes about. With limited remaining
space for normal stem cells to proliferate in, their ability replenish
bodily tissues is decreased. The link with increased endothelial stem cell
proliferation with higher HDL, which in turn is associated with reduced
mortality rates at advanced ages implies that there are safe ways to slow
shrinkage of stem cell niches.]

Aging Cell. 2006 Apr;5(2):139-152.
The aging neurogenic subventricular zone.
  Summary In the adult mouse brain, the subventricular zone (SVZ) is a
neurogenic stem cell niche only 4-5 cell diameters thick. Within this
narrow zone, a unique microenvironment supports stem cell self-renewal,
gliogenesis or neurogenesis lineage decisions and tangential migration of
newly generated neurons out of the SVZ and into the olfactory
bulb. However, with aging, SVZ neurogenesis declines. Here, we examine
the dynamic interplay between SVZ cytoarchitecture and neurogenesis
through aging. Assembly of high-resolution electron microscopy images of
corresponding coronal sections from 2-, 10- and 22-month-old mice into
photomontages reveal a thinning of the SVZ with age. Following a 2-h BrdU
pulse, we detect a significant decrease in cell proliferation from 2 to
22 months. Neuroblast numbers decrease with age, as do transitory
amplifying progenitor cells, while both SVZ astrocytes and adjacent
ependymal cells remain relatively constant. At 22 months, only residual
pockets of neurogenesis remain and neuroblasts become restricted to the
anterior dorsolateral horn of the SVZ. Within this dorsolateral zone many
key components of the younger neurogenic niche are maintained; however, in
the aged SVZ, increased numbers of SVZ astrocytes are found interposed
within the ependyma. These astrocytes co-label with markers to ependymal
cells and astrocytes, form intercellular adherens junctions with
neighboring ependymal cells, and some possess multiple basal bodies
of cilia within their cytoplasm. Together, these data reveal an
age-related, progressive restriction of SVZ neurogenesis to the
dorsolateral aspect of the lateral ventricle with increased numbers of
SVZ astrocytes interpolated within the ependyma.

Dev Biol. 2006 Mar 20; [Epub ahead of print]
Satellite-cell pool size does matter: Defining the myogenic potency of
aging skeletal muscle.
  The deteriorating in vivo environment is thought to play a major role
in reduced stem cell function with age. The capacity of stem cells to
support tissue maintenance depends not only on their response to cues
from the surrounding niche, but also on their abundance. Here, we
investigate satellite cell (myogenic stem cell) pool size and its
potential to participate in muscle maintenance through old age. The
numbers and performance of mouse satellite cells have been analyzed using
molecular markers that exclusively characterize quiescent satellite cells
and their progeny as they transit through proliferation, differentiation
and generation of reserve cells. The study establishes that abundance of
resident satellite cells declines with age in myofibers from both fast-
and slow-twitch muscles. Nevertheless, the inherent myogenic potential of
satellite cells does not diminish with age. Furthermore, the aging
satellite cell niche retains the capacity to support effective myogenesis
upon enrichment of the mitogenic milieu with FGF. Altogether, satellite
cell abundance, but not myogenic potential, deteriorates with age. This
study suggests that the population of satellite cells that participate in
myofiber maintenance during routine muscle utilization is not fully
replenished throughout life.

DNA Cell Biol. 2006 Feb;25(2):69-78.
How does cellular senescence prevent cancer?
  It is widely believed that cellular senescence is a tumor suppressor
mechanism; however, it has not been understood why it is advantageous for
organisms to retain mutant cells is a postmitotic state rather than
simply eliminating them by apoptosis. It has recently been proposed that
the primary role of cellular senescence is in mitotic compartments of
fixed size in which spatial considerations dictate that a deleted cell is
replaced by a neighboring cell. In these situations, rather than
eliminating the neoplastic clone, deletion of mutant cells can
paradoxically lead to their increased turnover. If mutant cells become
senescent, then the compartment is instead progressively filled by
senescent cells until the mutant clone is eliminated. Since most of the
genetic alterations responsible for malignancy arise in stem cells, this
mechanism may have particular relevance to the stem cell niche. In this
article the implications of this hypothesis are examined in detail and
related to experimental results. It is further proposed here that
blockage of stem cell niches by senescent stem cells may account for some
of the functional alterations observed in stem cell compartments at
old age. Clearly, the existence of senescent stem cells is central to the
proposed hypothesis, and although there is preliminary evidence for this
assertion it has yet to be proven in vivo. An experimental strategy
involving double labeling of stem cells with a nucleotide label is
described that can address this question.

Science. 2005 Feb 4;307(5710):720-4. Epub 2004 Dec 23.
Mechanisms of hair graying: incomplete melanocyte stem cell maintenance
in the niche.
  Hair graying is the most obvious sign of aging in humans, yet its
mechanism is largely unknown. Here, we used melanocyte-tagged transgenic
mice and aging human hair follicles to demonstrate that hair graying is
caused by defective self-maintenance of melanocyte stem cells. This
process is accelerated dramatically with Bcl2 deficiency, which causes
selective apoptosis of melanocyte stem cells, but not of differentiated
melanocytes, within the niche at their entry into the dormant
state. Furthermore, physiologic aging of melanocyte stem cells was
associated with ectopic pigmentation or differentiation within the niche,
a process accelerated by mutation of the melanocyte master
transcriptional regulator Mitf.

Int J Mol Med. 2006 Feb;17(2):203-8.
In vitro isolation of circulating endothelial progenitor cells is related
to the high density lipoprotein plasma levels.
  Circulating endothelial progenitor cells (EPCs) play an important role
in post natal neovascularization. High density lipoproteins (HDL) protect
the vascular wall from atherosclerosis. The role exerted by HDL on EPCs
physiology is unknown. In this study we investigated whether the levels
of plasma HDL can modulate the number of EPCs. The number of EPCs was
evaluated in 24 subjects as the number of endothelial colony-forming unit
(e-CFU) growth in culture. The number of AC133 positive progenitor cells
present in the gate of the CD34 bright positive lymphocytes was also
evaluated. Plasma levels of HDL, triglycerides and total cholesterol/HDL
cholesterol ratio correlated with the number of e-CFU (r=0.62,
P=0.006; r=-0.54, P=0.019, and r=-0.61, P=0.007 respectively), but not
with the number of CD34/AC133 positive progenitor cells. In vitro, the
incubation of the mononuclear cellular fraction with HDL did not increase
the number of e-CFU in culture, whereas LDL and VLDL reduced the number
of e-CFU. Our results indicate that human HDL plasma levels directly
relate to the number of circulating endothelial progenitor cells that can
be isolated in vitro, as determined by the number of e-CFU.

Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16789-94. Epub 2005 Nov 7.
Molecular evidence for arterial repair in atherosclerosis.
  Atherosclerosis is a chronic inflammatory process and progresses
through characteristic morphologic stages. We have shown previously that
chronically injecting bone-marrow-derived vascular progenitor cells can
effect arterial repair. This repair capacity depends on the age of the
injected marrow cells, suggesting a progressive decline in progenitor cell
function. We hypothesized that the progression of atherosclerosis
coincides with the deteriorating repair capacity of the bone
marrow. Here, we ascribe patterns of gene expression that accurately and
reproducibly identify specific disease states in murine
atherosclerosis. We then use these expression patterns to determine the
point in the disease process at which the repair of arteries by competent
bone marrow cells ceases to be efficient. We show that the loss of the
molecular signature for competent repair is concurrent with the
initiation of atherosclerotic lesions. This work provides a previously
unreported comprehensive molecular data set using broad-based analysis
that links the loss of successful repair with the progression of a
chronic illness.

Circulation. 2005 Jun 7;111(22):2981-7. Epub 2005 May 31.
Reduced number of circulating endothelial progenitor cells predicts
future cardiovascular events: proof of concept for the clinical
importance of endogenous vascular repair.
  BACKGROUND: The maintenance of endothelial integrity plays a critical
role in preventing atherosclerotic disease progression. Endothelial
progenitor cells (EPCs) were experimentally shown to incorporate into
sites of neovascularization and home to sites of endothelial
denudation. Circulating EPCs may thus provide an endogenous repair
mechanism to counteract ongoing risk factor-induced endothelial injury
and to replace dysfunctional endothelium. METHODS AND RESULTS: In 120
individuals (43 control subjects, 44 patients with stable coronary artery
disease, and 33 patients with acute coronary syndromes), circulating EPCs
were defined by the surface markers CD34+KDR+ and analyzed by flow
cytometry. Cardiovascular events (cardiovascular death, unstable angina,
myocardial infarction, PTCA, CABG, or ischemic stroke) served as outcome
variables over a median follow-up period of 10 months.
Patients suffering from cardiovascular events had significantly lower
numbers of EPCs (P<0.05). Reduced numbers of EPCs were associated with a
significantly higher incidence of cardiovascular events by Kaplan-Meier
analysis (P=0.0009). By multivariate analysis, reduced EPC levels were a
significant, independent predictor of poor prognosis, even after
adjustment for traditional cardiovascular risk factors and disease
activity (hazard ratio, 3.9; P<0.05). CONCLUSIONS: Reduced levels of
circulating EPCs independently predict atherosclerotic disease
progression, thus supporting an important role for endogenous vascular
repair to modulate the clinical course of coronary artery disease.

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