|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online 30 May 2006
doi: 10.1242/dev.02407
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Review |
1 Department of Cell Biology, Duke University Medical Center, Durham, NC 27710,
USA.
2 Program in Stem Cell Research, Duke University Medical Center, Durham, NC
27710, USA.
3 Department of Pediatrics, Duke University Medical Center, Durham, NC 27710,
USA.
* Author for correspondence (e-mail: b.hogan{at}cellbio.duke.edu)
SUMMARY
Most reviews of adult stem cells focus on the relatively undifferentiated cells dedicated to the renewal of rapidly proliferating tissues, such as the skin, gut and blood. By contrast, there is mounting evidence that organs and tissues such as the liver and pancreatic islets, which turn over more slowly, use alternative strategies, including the self-renewal of differentiated cells. The response of these organs to injury may also reveal the potential of differentiated cells to act as stem cells. The lung shows both slow turnover and rapid repair. New experimental approaches, including those based on studies of embryonic development, are needed to identify putative lung stem cells and strategies of lung homeostasis and repair.
Introduction
Throughout adult life, multicellular organisms must generate new cells to maintain the structure and function of their tissues. In young animals, tissue damage can usually be repaired quickly, but this natural capacity may fail after repeated challenges and with age. Diseases such as cancer may usurp and exploit the mechanisms by which the body normally rebuilds itself. These considerations drive us to understand the mechanisms by which adult organs normally achieve tissue homeostasis and repair. The emerging picture is that different organs use different strategies to renew themselves, and that more diversity and flexibility underpin these renewal processes than previously imagined.
Some organs, such as hair follicles, blood and gut, which constantly renew
themselves throughout life, contain adult stem cells that are morphologically
unspecialized, have a relatively low rate of division and are topologically
restricted to localized regions known as `niches' that tightly regulate their
behavior (Fuchs et al., 2004
;
Lanza, 2006). These
`dedicated' stem cells (see Box
1) undergo long-term self-renewal. They also produce a population
of transit amplifying (TA) daughter cells (see
Box 1) that have a high rate of
proliferation, can self-renew over the short term and give rise to precursors
of all or many of the differentiated cell types of the organ. These concepts
are now well established (Fig.
1). However, recent research has emphasized that the classical
hierarchy of the tissue-specific stem cell, TA cells and differentiated cells
is not always rigid and irreversible
(Raff, 2003). For example, the
commitment of cells to a specific fate may occur gradually, so that if stem
cells are ablated, some early TA cells may enter the empty niche and function
as stem cells (Kai and Spradling,
2004; Potten,
2004). TA cells may also be able to change their fate to give rise
to cells of another tissue type when exposed to appropriate signals. One
striking example occurs when cells from the central cornea of the adult rodent
eye, well away from any stem cells, are grafted onto dermis from embryonic
skin. Over several days they proliferate, express different genes and generate
hair follicles and sebaceous glands, presumably with associated stem cells
(Pearton et al., 2005). This
process is known as `transdifferentiation' - a term that needs careful use
according to its context (see Box
2).
In contrast to rapidly renewing organs such as the skin and gut, some
organs apparently maintain themselves without the aid of an undifferentiated
stem cell population. Evidence for this concept comes from recent experiments
in which insulin-producing ß-cells of the adult mouse pancreas were
labeled with a heritable genetic marker and followed during normal turnover
and regeneration after partial pancreatectomy
(Dor et al., 2004). Likewise,
in the liver, turnover and regeneration after hepatectomy involves the
division of differentiated hepatocytes. However, if hepatocyte proliferation
is inhibited, interlobular bile duct cells can replenish the hepatocyte
population (Alison et al.,
2004). Such observations have engendered the concept of
`facultative' stem cells - normally quiescent differentiated cells that can
act as stem cells after injury, perhaps by recapitulating processes that are
active during development (see Box
1).
The adult lung is a vital and complex organ that normally turns over very slowly. The epithelial cells that line the airways are constantly exposed to potential toxic agents and pathogens in the environment, and they must therefore be able to respond quickly and effectively to both cellular damage and to the local production of immune cytokines. Over the years, several experimental protocols have been developed in mice that mimic the injuries and rapid repair processes elicited in the lung by environmental challenges. The picture that is emerging from these models is that different regions of the respiratory system - the trachea and large airways, and the distal bronchioles and alveoli - use different kinds of stem cells and strategies for maintenance and repair. Moreover, there is evidence that differentiated epithelial cell types are able to proliferate and transdifferentiate in response to some conditions. However, the precise mechanisms involved in any of these processes are still very unclear.
| Box 1. A glossary Dedicated stem cell A relatively undifferentiated cell present in the adult organ, usually in localized niches. It normally divides infrequently; is capable of both long-term (`lifetime') self-renewal and of giving rise to daughter cells that differentiate into one or more specialized cell type; and it functions in both tissue homeostasis and repair. Facultative stem cell Differentiated cell that is normally quiescent but responds to injury by dividing and self-renewing, and giving rise to progeny that differentiate into one or more cell types. Metaplasia Strictly, the process by which a stem or progenitor cell of one tissue switches to become a progenitor of cells of another tissue type. Post-mitotic differentiated cell A cell that can no longer divide and must be replenished during normal turnover or injury. Progenitor cell Either a cell in the developing organ, usually multipotent, that is the source of an initial population of adult cells before turnover begins, or, more loosely, a cell that gives rise to another cell. Cell lineage relationships during development may not necessarily reflect those that occur during repair. Self-renewing differentiated cell Differentiated cell that divides and self-renews over the long term. Functions in both normal tissue homeostasis and in response to injury. Transdifferentiation See Box 2. Transit amplifying (TA) cell An intermediate between a dedicated stem cell and its final differentiated progeny. Can proliferate, self-renew over the short term and give rise to one or more differentiated cell type.
|
This review summarizes some recent findings, and outlines the challenges
and opportunities for future research into lung turnover and repair. These
findings are likely to be relevant to other organ systems that do not exactly
fit the well-described examples of skin/bone marrow/gut and islets/liver. In
particular, we suggest how concepts and tools familiar to developmental
biologists may help elucidate some of the outstanding problems. Examples
include the use of new technologies for lineage analysis in mice
(Metzger and Chambon, 2001),
and tissue recombination experiments to test the developmental potential of
isolated cells (Pearton et al.,
2005; Xin et al.,
2003; Xin et al.,
2005). Furthermore, work on the reciprocal interactions between
mesenchymal, endothelial and epithelial cells during development will inform
studies on the interplay between niche cells and stem cells in adult tissues
(Lammert et al., 2003).
Finally, studies into the role of cell shape changes, asymmetric cell division
and cell-matrix interactions in regulating gene expression in the embryo may
help us to elucidate the changes that are taking place in adult tissues when
they are undergoing repair and regeneration
(Keller, 2005;
Li et al., 2003;
Nguyen et al., 2005).
|
The lung has a complex three-dimensional structure that features major
differences along its proximodistal axis in terms of the composition of the
endoderm-derived epithelium (Fig.
2). The trachea and primary lung buds arise by different
morphogenetic processes from contiguous regions of the embryonic foregut
(Cardoso and Lu, 2006). In the
adult mouse trachea and primary bronchi (cartilaginous airways), the luminal
epithelium contains two main columnar cell types: ciliated cells and
Clara-like cells (Fig. 2). The
latter produce secretoglobins, the most abundant of which is Scgb1a1 (also
known as CCSP, CC10 or CCA). A small number of innervated neuroendocrine (NE)
cells are also present. In the adult mouse, mucous-producing cells are
restricted to a few submucosal glands in the upper airway. The epithelium of
the submucosal glands is continuous with the luminal epithelium and contains
ciliated and basal cells. A distinguishing feature of the cartilaginous
airways is that they contain a discontinuous population of relatively
unspecialized basal cells that express p63 (Trp63 - Mouse Genome Informatics)
and specific keratins (K14 and K5). These cells do not appear in the trachea
until around birth and after the differentiation of ciliated and secretory
cells. Tracheas of p63-/- embryos lack basal cells but do
have a columnar epithelium that contains predominantly ciliated cells
(Daniely et al., 2004).
In the more distal airways (small bronchi and bronchioles)
(Fig. 2), the epithelium is
columnar. Clara cells predominate over ciliated cells and there are more NE
cells than in the trachea. Importantly, however, there are no basal cells, so
that they cannot be involved in local turnover and repair
(Pack et al., 1981).
The most distal region of the lung is organized into a complex system of alveoli (Fig. 2). There are two types of epithelial cell here: type I cells, which provide the thin-walled gas exchange surface; and cuboidal type II cells. The latter contain numerous secretory vesicles (lamellar bodies) filled with surfactant material, including surfactant-associated protein C or Sftpc. The transitional region between the terminal bronchioles and the alveoli is known as the bronchioalveolar duct junction (BADJ).
Currently, the identification of these different epithelial cell types
relies largely on the expression of secreted proteins, which is not ideal for
sorting cells by flow cytometry. Progress is being made in finding better
markers for distinguishing and sorting different lung epithelial cell types
(e.g. Kim et al., 2005;
Reynolds et al., 2002).
However, there may be important subpopulations of cells that are missed at
present. We are a long way from having a molecular signature for each of the
cell types of the adult lung and there is a pressing need for a comprehensive
public database of cell type gene expression.
| Box 2. Transdifferentiation This refers to the transformation of one well-defined type of fully differentiated cell into another well-defined type. In this review, we refer to `direct transdifferentiation' as the transformation from one phenotype to another without an obligatory round of cell proliferation. `Transdifferentiation with proliferation' requires at least one intervening round of cell proliferation. The direct mechanism is more likely to involve the transient existence of a cell that co-expresses differentiation markers of both old and new phenotypes. By contrast, the mechanism that involves proliferation is more likely to involve the transient existence of a `de-differentiated' cell, which has a pattern of gene expression that is different from either the initial or final cell type. Some stem cell researchers have applied the term `transdifferentiation' to `the ability of a particular cell of one tissue...including stem or progenitor cells, to differentiate into a cell type characteristic of another tissue' (see www.isscr.org/glossary/index.htm). This much looser definition really describes a phenomenon that is known as `transdetermination' when it occurs in embryos and as `metaplasia' when it occurs in adults.
|
Lung turnover is normally slow
Estimates for the turnover time of the mouse airway epithelium vary widely.
This may reflect differences in the health and pathogen status, strain and age
of individuals (Wells, 1970).
Lung size in rodents keeps constant pace with body size, so that mouse lungs
continue to grow throughout life, although the rate slows with age
(Thurlbeck, 1975). However,
the consensus is that the turnover time of the tracheal-bronchial epithelium
of adult rodents is more than 100 days (4 months)
(Blenkinsopp, 1967). By
comparison, the gut, which is also endodermally derived, has an estimated
turnover time of 4 days.
The clearest studies of steady-state maintenance of the lung have involved
pulse/chase experiments with tritiated thymidine ([3H]-TdR). In the
proximal airways (trachea/bronchi), this approach has identified basal and
secretory (Clara-like) cells as the dividing cells and the ciliated cells as
their descendents (Breuer et al.,
1990; Donnelly et al.,
1982; Kauffman,
1980). However, this method cannot be used to determine
conclusively whether it is the basal or Clara cells that give rise to the
ciliated cells and whether the relationship is the same in different regions
of the lung. ([3H]-TdR incorporation at steady state in airways
lacking basal cells has not been closely studied.) The best way to define
lineage relationships is to use Cre/lox genetic labeling to follow the
descendants of specific cells. For example, the inducible expression of Cre
recombinase could be used to activate a heritable reporter gene specifically
in Scgb1a1-expressing (Clara and Clara-like) cells and to ask which cell types
subsequently acquire the label. In addition, one can ask whether there is a
substantial dilution of the label in the population over time, as expected if
Clara-like cells are continually replaced from a pool of unlabeled stem cells
(Dor et al., 2004).
`Mucous metaplasia' in the adult lung
Genetic lineage tracing would also help to clarify the current confusion
over the mechanisms that underlie the phenomenon loosely called `mucous
metaplasia' that is seen in adult mice challenged with aerosolized allergens,
and probably involves the local production of inflammatory cytokines, such as
interleukin 13 (Williams et al.,
2006). In the normal adult mouse lung, there are few
mucous-secreting cells outside the submucosal glands, although some are seen
in the early postnatal lung (Rawlins and
Hogan, 2005). However, a few days after antigen exposure, large
numbers can be found in the trachea and large airways. One idea is that these
are derived by the `direct transdifferentiation' (see
Box 2) of ciliated cells or
Clara cells, as cells have been observed by electron microscopy that contain
both cilia and large numbers of mucous-containing vesicles
(Evans et al., 2004;
Hayashi et al., 2004;
Reader et al., 2003;
Tyner et al., 2006). Some of
the other hypotheses are that the formation of mucous cells involves the
differentiation of progenitor cells, and/or the proliferation and
de-differentiation of differentiated cells. Distinguishing between these
mechanisms would improve our understanding of the origin of the large numbers
of goblet cells that are found in humans with conditions such as chronic
asthma.
Evidence for lung stem cells from ex vivo studies
In the hematopoetic system, it is possible to test the ability of cells to
restore all the blood cell lineages by injecting them intravenously into an
irradiated host. Likewise, dissociated hepatocytes can repopulate the damaged
liver after injection into the portal vein, and clonal analysis can be
achieved in this system using retrovirally labeled cells
(Overturf et al., 1999).
Recent studies have shown that a complete mouse mammary gland can be grown
from a single adult epithelial cell implanted into a mammary fat pad
(Shackleton et al., 2006).
There are currently no such in vivo tests for the potency of lung cells.
However, two ex vivo systems have been used to examine the regenerative
potential of isolated lung epithelial cells: the rat tracheal xenograft model
and cell culture. These systems are particularly useful because they can be
applied to the study of human adult and fetal airway epithelial cells,
including tracheal cells and nasal polyps, as discussed below
(Dupuit et al., 2000).
Rat tracheal xenograft model
In this model, epithelial cells isolated from a donor airway epithelium are
dissociated and seeded onto the surface of a host rat trachea that has been
denuded of endogenous epithelial cells by freeze-thawing. The trachea is then
grafted subcutaneously into an immunodeficient mouse. Several weeks later, a
well-differentiated, normal airway epithelium with a few submucosal glands is
restored (Fig. 3); whether this
organization can be maintained over the long term is not known. Two kinds of
studies have been carried out with this model. First, retroviral labeling has
been used to follow retrospectively the proliferative and differentiation
potential of single epithelial cells within the seeding population. When adult
human bronchial epithelial cells were used, the largest and most frequently
labeled clones contained basal, ciliated and goblet cells. However, clones
consisting of subsets of these cell types also formed
(Engelhardt et al., 1995).
These results illustrate that there are both multipotent cells and
lineage-restricted progenitor cells in the human airway epithelium.
The second experimental approach has been to sort the donor cells into
basal and non-basal populations and then to follow their ability to
reconstitute the surface epithelium. The results from such studies have so far
been very variable. Some suggest that both populations can restore the
tracheal epithelium equally well
(Avril-Delplanque et al., 2005;
Liu et al., 1994). However,
others have found that only columnar cells
(Johnson and Hubbs, 1990) or
only basal cells (Ford and Terzaghi-Howe,
1992) can restore all of the epithelial cell types. These
discrepancies may be due to differences in sorting methods, donor species or
the length of time allowed for epithelial repopulation. In spite of these
differences, and the urgent need for better methods of sorting tracheal cell
populations, these results suggest that both the columnar and basal cells can
restore the tracheal epithelium in the xenograft model.
|
). The
potential of this grafting technique is well illustrated by recent studies on
stem cells and regeneration in the postnatal prostate epithelium, another
endodermally derived tissue. By combining genetically marked and unmarked
prostate epithelial cells with embryonic mesenchyme, it has been shown that an
entire tubule could be derived from a single cell and that cells with
regenerative capacity can be sorted based on surface markers
(Xin et al., 2003;
Xin et al., 2005). Like the
trachea, the prostate contains p63-positive basal cells, although these are
present before the appearance of differentiated secretory cells.
Interestingly, if endodermal cells from a p63-null mouse mutant
prostate are used in the graft, a proportion of the epithelial cells
differentiate abnormally into mucous-producing cells
(Kurita et al., 2004;
Signoretti et al., 2005). This
unexpected finding suggests that in the prostate, p63 is required in the basal
cells to maintain the normal organization and fate of the columnar cells.
|
). The development of in vitro clonogenic assays for lung
epithelial cells is only in its infancy. The challenge has been to devise
culture conditions in which adult airway epithelial cells, and in particular
mouse cells, marked with a cell-autonomous genetic reporter, can reproducibly
differentiate into secretory, ciliated and basal cells. One system involves
seeding dissociated airway epithelial cells on to membranes and culturing them
at an air-liquid interface. By mixing genetically marked tracheal cells
isolated from Rosa26 mice (which ubiquitously express lacZ)
with unmarked `stuffer' cells, it has been possible to identify colonies
derived from single cells. In these experiments, the largest colonies (derived
from about 0.1% of the population) contain differentiated columnar epithelial
cells, including ciliated cells, as well as basally orientated cells
(Schoch et al., 2004). This
assay system was also used to compare the proliferative capacity of basal and
non-basal cells. Basal cells, sorted by flow cytometry on the basis of the
expression of eGFP from a keratin5 promoter, formed the larger
colonies. Taken together, the results support the idea that the tracheal basal
cells are stem cells in vivo. One of the main limitations of this assay is
that it does not support the reproducible differentiation of all epithelial
cell types, but future improvements may come from modifying culture conditions
and using feeder layers.
In vitro culture has recently been used to test the differentiation
potential of putative stem cells located at the BADJ of the mouse lung
(Fig. 2). These cells have been
termed bronchioalveolar stem cells or BASCs
(Kim et al., 2005) (as
discussed later in the review). Small numbers of cuboidal cells have been
identified immunohistochemically in the BADJ that co-express both
secretoglobin 1a1 (Scgb1a1, a secreted product of Clara cells) and surfactant
protein C (Sftpc). Sftpc is a major secreted product of type II alveolar cells
but is expressed, at low levels, by early embryonic lung epithelial cells
(Khoor et al., 1994). The
BASCs are also positive for the surface glycoprotein, CD34. This is commonly,
but not exclusively, expressed on somatic stem cells, for example, on mouse
hair follicle and hematopoietic stem cells. The Sftpc/Scgb1a1-positive cells
were then cell sorted, based on being Sca1 positive, CD34 positive and being
CD45 negative, Pecam negative. Single cells were cultured on a feeder layer of
mouse embryonic fibroblasts, expanded and then cultured on a Matrigel
substrate where they gave rise to cells that expressed markers for either
Clara cells, type I cells or type II cells. Taken together, these results
suggest that BASCs, as defined by their surface markers, have the potential to
divide in culture and are multipotent. What is needed now is evidence that
these cells function as stem cells in vivo. The authors do show that
dual-positive Sftpc/Scgb1a1 cells are the first cells to proliferate in the
naphthalene lung injury model, which is described below. Moreover, cells with
the same characteristics are expanded in adenocarcinomas of the
bronchioalveolar junction that are induced by activated K-ras expression
(Kim et al., 2005). However,
although the identification of putative BASCs is very promising, the evidence
for their self-renewal and multipotency in vivo is still preliminary.
The response of lung epithelial cells to injury
Although the normal lung turns over very slowly, it is able to respond
rapidly to specific injuries that mimic damage caused by environmental or
infectious agents. There is some strain dependence in the efficiency of this
injury/regenerative response (e.g. Lawson
et al., 2002), but each model elicits a different repair program
that can reveal the proliferative and differentiation potential of the
surviving cells. The experiments are frequently interpreted as showing the
presence of stem cells in the adult lung. Although in some cases this may be
correct, other interpretations have not always been excluded. The evidence for
involvement of different cell types in the turnover and repair of the proximal
and distal lung is summarized in Figs
4 and
5.
|
; Plopper et al.,
1992), the sequence of events is approximately as follows. Within
a few hours nearly all the Clara cells die, leaving intact the few Clara cells
that do not express Cyp2f2 and are therefore resistant
(Fig. 6). The ciliated cells
quickly spread out, or squamate, under the dying Clara cells in an attempt to
cover the basal lamina and maintain the permeability barrier of the
epithelium. In doing so, they internalize and disassemble their cilia in a
very specific way (Lawson et al.,
2002; Van Winkle et al.,
1999). Cell proliferation begins 2-3 days after injury, and by 2-4
weeks, the epithelium has returned to steady state
(Stripp et al., 1995;
Van Winkle et al., 1995). The
NE cells appear to increase in number after the injury through self-renewal
(Reynolds et al., 2000a;
Reynolds et al., 2000b;
Stevens et al., 1997), a
process that may be driven by sonic hedgehog (Shh) signaling
(Watkins et al., 2003).
However, different mechanisms appear to operate for the renewal of the Clara
cells and increase in ciliated cells, depending on the region of the lung in
which the repair occurs, as discussed below.
Response to naphthalene injury in the proximal lung In the trachea and main
bronchi, there is good evidence that basal cells function as stem cells in
repairing the destruction of the Clara cells by naphthalene. This evidence
comes from the first in vivo genetic lineage labeling studies to be carried
out in the adult lung, illustrating the power of this approach
(Hong et al., 2004a;
Hong et al., 2004b). A
tamoxifen-inducible Cre recombinase under the control of a cytokeratin 14
(K14; Krt1-14-Mouse Genome Informatics) promoter was
activated in mice after the naphthalene injury to drive genomic rearrangement
of the Rosa26R reporter allele. This results in constitutive
lacZ expression in a subset of the K14-expressing cells, and
all of their descendents. At the end of the recovery period, the repaired
epithelium contained patches of ß-galactosidase (lacZ)-positive
epithelial cells. These patches contained three different cell types:
K14-positive basal cells, Clara-like cells and ciliated cells. This suggests
that K-14-positive cells can self-renew and produce cells of other lineages in
response to injury; in other words, they can behave like dedicated stem cells.
It is tempting to conclude that the K14-positive, proliferating cells are
basal cells, because under steady-state conditions K14 is expressed
exclusively by this population. However, other studies have shown that
proliferating cells in repairing tracheal epithelium can activate K14
de novo, even when they are not derived from basal cells
(Liu et al., 1994). As the
tamoxifen was given after the injury, these experiments strongly support the
idea that basal cells are stem cells but they do not formally rule out a role
for other cells in which K14 expression is activated during the injury
response. In addition, they do not exclude a role for columnar cells
(including ciliated cells) in the repair process.
|
|
;
Stripp et al., 1995) or at the
BADJs, where there are very few NEBs
(Giangreco et al., 2002;
Hong et al., 2001;
Stripp et al., 1995). The
latter may be the same as the putative BASCs discussed earlier that co-express
Sftpc and Scgb1a1, and proliferate after naphthalene injury
(Kim et al., 2005) (Figs
2,
5). ClaraV cells are
resistant to naphthalene injury because they do not express the enzyme Cyp2f2,
a member of the cytochrome P450 family that converts naphthalene to a toxic
product. This lack of expression may reflect a less differentiated state of
the cells relative to the majority of the Clara cell population. If
ClaraV (and putative BASCs) can be shown to self-renew and give
rise to differentiated progeny during the slow turnover of the normal lung,
then they could be classified as dedicated stem cells, rather than as
facultative stem cells that are called into action only in response to injury
(see Box 1). They would differ
from more `classical' undifferentiated stem cells
(Fig. 1) only in that they
express markers of differentiated cell types (calcitonin gene-related peptide
and Scgb1a1 in the case of ClaraV cells, and Sftpc and Scgb1a1 in
the case of BASCs). The potential role of ClaraV cells in
homeostasis and repair of the distal lung is illustrated in
Fig. 7.
|
;
Reynolds et al., 2000b). After
this procedure, the airways could not be repaired. This result argues that
ciliated cells cannot give rise to Clara cells, but it does not exclude the
self-renewal of ciliated cells. Indeed, the role of ciliated cells in the
response to naphthalene injury is contentious. In one set of studies, no
evidence for proliferation was seen
(Reynolds et al., 2000a).
However, others have claimed that the squamated (flattened) ciliated cells do
indeed proliferate 48 hours after naphthalene injury
(Park et al., 2005). Moreover,
they argue that some of these cells undergo transdifferentiation to
non-ciliated columnar cells. In other words, the authors of this study claim
that, after injury, the ciliated cells can both self-renew and give rise to
another lineage, i.e. they behave as stem cells. If ciliated cells do not
normally self-renew and are quiescent, they could be considered, under these
conditions, to be facultative stem cells. The only way to determine for
certain whether ciliated cells do indeed transdifferentiate after naphthalene
injury, and whether ClaraV and BASCs are the only cells that can
function as stem cells in the steady state and after injury is to carry out
lineage tracing studies in vivo.
Repair after damage by inhaled oxidants
Although naphthalene injury has been used to study the regeneration of
Clara cells in the lung, other models specifically destroy ciliated cells or
type I alveolar cells. These include inhalation of oxidants such as
NO2 and ozone (which selectively kill ciliated cells) and
administration of the chemotherapy agent, bleomycin (which kills type I
cells). To summarize briefly (see Figs
4 and
5), these studies suggest that
ciliated cells can be regenerated from Clara cells, and type II cells give
rise to type I cells. Again, these findings need to be confirmed by in vivo
lineage studies (Aso et al.,
1976; Barth and Muller,
1999; Evans et al.,
1975; Evans et al.,
1986). It is also unclear whether all type II cells have the
capacity to give rise to type I cells, or only those in specific regions, such
as BASCs.
Injury by sulfur dioxide
Both the naphthalene and oxidant exposure models injure only subsets of
epithelial cells in the lung. To produce more extensive damage, investigators
have used SO2 inhalation in mice
(Borthwick et al., 2001). This
destroys the majority of the pseudostratified epithelial cells in the upper
trachea, leaving behind protected cells in the surface layer and submucosal
glands, and in patches of denuded basement membrane. Within 7 days, full
repair has taken place and a morphologically normal epithelium is
re-established. To identify any dedicated stem cells in this model, the
investigators relied on the assumption that such cells divide infrequently and
retain a DNA label over a long chase period. They therefore exposed
experimental animals to repeated rounds of SO2 and BrdU, so that
almost every epithelial cell became labeled. After a chase of up to 95 days
(
3.5 months), small groups of label retaining cells (LRCs) were localized
either to the collecting ducts of the submucosal glands or to the surface
epithelium in the inter-cartilage regions. Morphologically, the LRCs in both
regions appear to be basal cells. Evidence that these cells actually
proliferate in response to injury, self renew and give rise to ciliated and
Clara cells in vivo awaits lineage-tracing studies. However, the idea is
supported by the cell culture and naphthalene recovery experiments discussed
earlier. Moreover, a xenograft model in which the surface epithelium was
completely denuded, leaving behind the submucosal glands, showed that cells in
the ducts of these glands can repopulate the entire tracheal surface
(Borthwick et al., 2001).
Potential niches for lung stem cells
In the experiments described above, LRCs appear to cluster in the
intercartilage regions, which are particularly well supplied with blood
vessels and nerves. Indeed, it has been suggested that these non-epithelial
cells are components of a special `tracheal niche' that regulates the activity
of dedicated stem cells (Borthwick et al.,
2001). More distally, it has been suggested that the NEBs may
serve as a niche for the ClaraV cells, and that the BADJ region may
serve as a niche for the putative BASCs
(Giangreco et al., 2002;
Reynolds et al., 2000a). Both
of these regions are well supplied with blood vessels, and the NEBs are
innervated. These ideas are certainly in line with studies in other systems
such as the hair follicle, intestine, bone marrow and brain, where there is
good molecular evidence for regulatory signaling between the stem cells and
surrounding (non-epithelial) cells
(Botchkarev and Sharov, 2004;
Calvi et al., 2003;
He et al., 2004;
Lie et al., 2005). For
example, many of the genes active in hair follicle stem cells are components
of the Wnt, Bmp and Fgf intercellular signaling pathways
(Rendl et al., 2005;
Tumbar et al., 2004). These
have been shown to play crucial roles in intercellular signaling in lung
development (Bellusci et al.,
1997; Cardoso and Lu,
2006; Del Moral et al.,
2006; Eblaghie et al.,
2006; Shu et al.,
2005; Weaver et al.,
2003; Weaver et al.,
2000) and are likely components of any localized stem cell niche
in the trachea and distal airways. However, it should also be noted that blood
vessels and nerves are closely associated with the basal lamina that underlies
the epithelium along the entire airway system. Consequently, signaling between
these two populations and also inflammatory cells could also regulate the
potential self-renewal of differentiated or TA cells during the response to
injuries and inflammation.
It is in this area of research - the control of stem cell behavior by the
niche - that developmental biology is likely to have a particularly strong
impact. For example, there is mounting evidence for the importance of
endothelial cell signaling to adult stem cells
(Paris et al., 2001;
Shen et al., 2004).
Developmentally, there are now clear examples of endothelial cells that
regulate the proliferation and differentiation of organ primordia (liver,
pancreas) and also organ morphogenesis (kidney)
(Jacquemin et al., 2006;
Lammert et al., 2003;
Matsumoto et al., 2001;
Yoshitomi and Zaret, 2004).
Similarly, developmental biologists have elucidated complex gene regulatory
networks involving crosstalk between a variety of signaling pathways that
control progenitor cell proliferation and differentiation
(Levine and Davidson, 2005).
It is clear that highly related networks of interacting genes and signaling
pathways regulate stem cell self-renewal versus differentiation and quiescence
versus proliferation (Ivanova et al.,
2002; Ramalho-Santos et al.,
2002); studies in one system can only promote understanding in the
other.
Role of other cell lineages in epithelial repair?
Several studies have suggested that cells from the bone marrow can
differentiate into lung epithelial cells after intravenous injection into a
mouse that has received a lung injury
(Kotton et al., 2001;
Krause et al., 2001;
Macpherson et al., 2005;
Theise et al., 2002). Indeed,
it has been claimed that these exogenous cells can transdifferentiate into
alveolar type II and I cells. Naturally, these findings have given rise to the
hope that human lung diseases will one day be treated using stem cells derived
from the bone marrow. However, these results in the lung, as in other tissues,
are still very controversial (Raff, 2004). The role of exogenous cells in lung
repair was recently tested using donor bone marrow-derived cells from a mouse
line carrying in its genome a transgene that drives GFP from a type II
alveolar cell-specific (Sftpc) promoter. Sophisticated imaging
techniques demonstrated that the bone marrow-derived cells did indeed engraft
in the lung at a low frequency. However, these cells did not express the
lung-specific transgene (Chang et al.,
2005). These data argue against the donor cells contributing
directly to Sftpc-expressing host lung epithelium.
In spite of their apparent inability to contribute to functional lung
epithelium directly, it is still possible that bone marrow-derived cells can
aid in the repair of chemically induced lung injury
(Ortiz et al., 2003;
Rojas et al., 2005). For
example, myelosupressed mice-treated with bleomycin and subsequently with an
injection of bone marrow derived-cells had a better survival rate and lung
morphology than controls (Rojas et al.,
2005). The exact role of the bone marrow-derived cells is not yet
clear, although their effect is apparently out of all proportion to the number
that actually engraft into the lung. Perhaps these cells can secrete factors
that affect the endogenous lung epithelial cells, raising the interesting
possibility that circulating cells are part of the stem cell `niche' discussed
above. Indeed, recent work on mechanical injury in the colon has demonstrated
that the macrophages (themselves activated by the natural gut microorganisms)
provide an essential signal to activate proliferation of the stem cells
(Pull et al., 2005). Such
studies are important for the lung because, in the short term at least, it may
be easier to modulate the composition of the niche to promote repair than to
provide exogenous cells to replace the injured epithelium.
Conclusions
The picture that is emerging from studies on the response of the lung to
injury is that the organ makes use of several different strategies for
homeostasis and repair. In the proximal lung (trachea and main bronchi) it is
likely that undifferentiated basal cells can function as classical stem cells,
both self-renewing and giving rise to ciliated and secretory cells. However,
Clara cells can also give rise to ciliated cells after these are damaged by
oxidants, and the potential self-renewal of Clara cells and even ciliated
cells in the steady state has not been ruled out. In the more distal lung,
where there are no basal cells, the evidence suggests that subpopulations of
Clara cells (ClaraV and BASCs) in specific micro-environments can
self-renew and give rise to different cell types after injury. Whether they
behave as dedicated stem cells in the steady state is not yet known, and
whether ciliated cells can proliferate and transdifferentiate, are still
unanswered questions (Fig. 7).
Finally, in the alveoli, damaged type I cells can be restored from type II
cells, although whether all type II cells have this capacity is not yet known.
The diversity of strategies for repair, and the different classes of stem
cells in the lung, are in sharp contrast to the situation in the intestine.
Here, only a few stem cells are present near the base of the crypts, and they
and the TA population derived from them appear to be responsible for
replenishing the entire epithelium. This difference probably reflects the fact
that cell turnover in the lung is normally very low, so that a conveyor belt
type mechanism for constantly and rapidly renewing the epithelium is not
required. However, when injury to the epithelium of the lung does occur it has
to be repaired as quickly as possible. In this case, a situation in which
multiple cell types can proliferate and function as progenitors for repair is
probably an advantage.
Although a general picture of epithelial turnover and repair in the lung is gradually emerging, many challenges still remain. For example, we have indicated in several sections the need for more phenotypic markers for lung cells to allow their unambiguous identification and efficient sorting by flow cytometry. There may still be important subpopulations of epithelial cells that are completely missed. We also need more genetic tools to follow cell fate and lineage relationships both in the embryo and the adult. Another pressing challenge is devising better systems to assay the developmental potential of isolated adult lung epithelial cells and rapidly testing the function of genes activated or repressed in the process of repair. Finally, we need to know more about the interactions between epithelial and non-epithelial cell populations during homeostasis and in response to injury. Answers to these and other questions are likely to come from many different directions. Among these are the application of ideas and principles derived from basic research in developmental biology.
ACKNOWLEDGMENTS
We thank Scott Randell, Barry Stripp and Jonathan Slack for helpful comments, images and discussion. Work in the authors' laboratory is supported by NIH-080517.
REFERENCES
Alison, M. R., Vig, P., Russo, F., Bigger, B. W., Amofah, E.,
Themis, M. and Forbes, S. (2004). Hepatic stem cells: from
inside and outside the liver? Cell Prolif.
37, 1-21.[CrossRef][Medline]
Aso, Y., Yoneda, K. and Kikkawa, Y. (1976).
Morphologic and biochemical study of pulmonary changes induced by bleomycin in
mice. Lab. Invest. 35,558
-568.[Medline]
Avril-Delplanque, A., Casal, I., Castillon, N., Hinnrasky, J.,
Puchelle, E. and Peault, B. (2005). Aquaporin-3 expression in
human fetal airway epithelial progenitor cells. Stem
Cells 23,992
-1001.[CrossRef][Medline]
Barth, P. J. and Muller, B. (1999). Effects of
nitrogen dioxide exposure on Clara cell proliferation and morphology.
Pathol. Res. Pract. 195,487
-493.[Medline]
Bellusci, S., Grindley, J., Emoto, H., Itoh, N. and Hogan, B.
L. (1997). Fibroblast growth factor 10 (FGF10) and branching
morphogenesis in the embryonic mouse lung. Development
124,4867
-4878.[Abstract]
Blenkinsopp, W. K. (1967). Proliferation of
respiratory tract epithelium in the rat. Exp. Cell
Res. 46,144
-154.[CrossRef][Medline]
Borthwick, D. W., Shahbazian, M., Krantz, Q. T., Dorin, J. R.
and Randell, S. H. (2001). Evidence for stem-cell niches in
the tracheal epithelium. Am. J. Respir. Cell Mol.
Biol. 24,662
-670.
Botchkarev, V. A. and Sharov, A. A. (2004). BMP
signaling in the control of skin development and hair follicle growth.
Differentiation 72,512
-526.[CrossRef][Medline]
Breuer, R., Zajicek, G., Christensen, T. G., Lucey, E. C. and
Snider, G. L. (1990). Cell kinetics of normal adult hamster
bronchial epithelium in the steady state. Am. J. Respir. Cell Mol.
Biol. 2,51
-58.[Medline]
Calvi, L. M., Adams, G. B., Weibrecht, K. W., Weber, J. M.,
Olson, D. P., Knight, M. C., Martin, R. P., Schipani, E., Divieti, P.,
Bringhurst, F. R. et al. (2003). Osteoblastic cells regulate
the haematopoietic stem cell niche. Nature
425,841
-846.[CrossRef][Medline]
Cardoso, W. V. and Lu, J. (2006). Regulation of
early lung development: questions, facts and controversies.
Development 133,1611
-1624.
Chang, J. C., Summer, R., Sun, X., Fitzsimmons, K. and Fine,
A. (2005). Evidence that bone marrow cells do not contribute
to the alveolar epithelium. Am. J. Respir. Cell Mol.
Biol. 33,335
-342.
Daniely, Y., Liao, G., Dixon, D., Linnoila, R. I., Lori, A.,
Randell, S. H., Oren, M. and Jetten, A. M. (2004). Critical
role of p63 in the development of a normal esophageal and tracheobronchial
epithelium. Am. J. Physiol. Cell Physiol.
287,C171
-C181.
Del Moral, P. M., Sala, F. G., Tefft, D., Shi, W., Keshet, E.,
Bellusci, S. and Warburton, D. (2006). VEGF-A signaling
through Flk-1 is a critical facilitator of early embryonic lung epithelial to
endothelial crosstalk and branching morphogenesis. Dev.
Biol. 290,177
-188.[CrossRef][Medline]
Donnelly, G. M., Haack, D. G. and Heird, C. S.
(1982). Tracheal epithelium: cell kinetics and differentiation in
normal rat tissue. Cell Tissue Kinet.
15,119
-130.[Medline]
Dor, Y., Brown, J., Martinez, O. I. and Melton, D. A.
(2004). Adult pancreatic beta-cells are formed by
self-duplication rather than stem-cell differentiation.
Nature 429,41
-46.[CrossRef][Medline]
Dupuit, F., Gaillard, D., Hinnrasky, J., Mongodin, E., de
Bentzmann, S., Copreni, E. and Puchelle, E. (2000).
Differentiated and functional human airway epithelium regeneration in tracheal
xenografts. Am. J. Physiol. Lung Cell Mol. Physiol.
278,L165
-L176.
Eblaghie, M. C., Reedy, M., Oliver, T., Mishina, Y. and Hogan,
B. L. (2006). Evidence that autocrine signaling through
Bmpr1a regulates the proliferation, survival and morphogenetic behavior of
distal lung epithelial cells. Dev. Biol.
291, 67-82.[CrossRef][Medline]
Engelhardt, J. F., Schlossberg, H., Yankaskas, J. R. and Dudus,
L. (1995). Progenitor cells of the adult human airway
involved in submucosal gland development. Development
121,2031
-2046.[Abstract]
Evans, C. M., Williams, O. W., Tuvim, M. J., Nigam, R., Mixides,
G. P., Blackburn, M. R., DeMayo, F. J., Burns, A. R., Smith, C., Reynolds, S.
D. et al. (2004). Mucin is produced by clara cells in the
proximal airways of antigen-challenged mice. Am. J. Respir. Cell
Mol. Biol. 31,382
-394.
Evans, M. J., Cabral, L. J., Stephens, R. J. and Freeman, G.
(1975). Transformation of alveolar type 2 cells to type 1 cells
following exposure to NO2. Exp. Mol. Pathol.
22,142
-150.[CrossRef][Medline]
Evans, M. J., Shami, S. G., Cabral-Anderson, L. J. and Dekker,
N. P. (1986). Role of nonciliated cells in renewal of the
bronchial epithelium of rats exposed to NO2. Am. J.
Pathol. 123,126
-133.[Abstract]
Ford, J. R. and Terzaghi-Howe, M. (1992).
Characteristics of magnetically separated rat tracheal epithelial cell
populations. Am. J. Physiol.
263,L568
-L574.[Medline]
Fuchs, E., Tumbar, T. and Guasch, G. (2004).
Socializing with the neighbors: stem cells and their niche.
Cell 116,769
-778.[CrossRef][Medline]
Giangreco, A., Reynolds, S. D. and Stripp, B. R.
(2002). Terminal bronchioles harbor a unique airway stem cell
population that localizes to the bronchoalveolar duct junction. Am.
J. Pathol. 161,173
-182.
Hayashi, T., Ishii, A., Nakai, S. and Hasegawa, K.
(2004). Ultrastructure of goblet-cell metaplasia from Clara cell
in the allergic asthmatic airway inflammation in a mouse model of asthma in
vivo. Virchows Arch.
444, 66-73.[CrossRef][Medline]
He, X. C., Zhang, J., Tong, W. G., Tawfik, O., Ross, J.,
Scoville, D. H., Tian, Q., Zeng, X., He, X., Wiedemann, L. M. et al.
(2004). BMP signaling inhibits intestinal stem cell self-renewal
through suppression of Wnt-beta-catenin signaling. Nat.
Genet. 36,1117
-1121.[CrossRef][Medline]
Hong, K. U., Reynolds, S. D., Giangreco, A., Hurley, C. M. and
Stripp, B. R. (2001). Clara cell secretory protein-expressing
cells of the airway neuroepithelial body microenvironment include a
label-retaining subset and are critical for epithelial renewal after
progenitor cell depletion. Am. J. Respir. Cell Mol.
Biol. 24,671
-681.
Hong, K. U., Reynolds, S. D., Watkins, S., Fuchs, E. and Stripp,
B. R. (2004a). Basal cells are a multipotent progenitor
capable of renewing the bronchial epithelium. Am. J.
Pathol. 164,577
-588.
Hong, K. U., Reynolds, S. D., Watkins, S., Fuchs, E. and Stripp,
B. R. (2004b). In vivo differentiation potential of tracheal
basal cells: evidence for multipotent and unipotent subpopulations.
Am. J. Physiol. Lung Cell Mol. Physiol.
286,L643
-L649.
Ivanova, N. B., Dimos, J. T., Schaniel, C., Hackney, J. A.,
Moore, K. A. and Lemischka, I. R. (2002). A stem cell
molecular signature. Science
298,601
-604.
Jacquemin, P., Yoshitomi, H., Kashima, Y., Rousseau, G. G.,
Lemaigre, F. P. and Zaret, K. S. (2006). An
endothelial-mesenchymal relay pathway regulates early phases of pancreas
development. Dev. Biol.
290,189
-199.[CrossRef][Medline]
Johnson, N. F. and Hubbs, A. F. (1990).
Epithelial progenitor cells in the rat trachea. Am. J. Respir. Cell
Mol. Biol. 3,579
-585.[Medline]
Kai, T. and Spradling, A. (2004).
Differentiating germ cells can revert into functional stem cells in Drosophila
melanogaster ovaries. Nature
428,564
-569.[CrossRef][Medline]
Kauffman, S. L. (1980). Cell proliferation in
the mammalian lung. Int. Rev. Exp. Pathol.
22,131
-191.[Medline]
Keller, R. (2005). Cell migration during
gastrulation. Curr. Opin. Cell Biol.
17,533
-541.[CrossRef][Medline]
Khoor, A., Stahlman, M. T., Gray, M. E. and Whitsett, J. A.
(1994). Temporalspatial distribution of SP-B and SP-C proteins
and mRNAs in developing respiratory epithelium of human lung. J.
Histochem. Cytochem. 42,1187
-1199.[Abstract]
Kim, C. F., Jackson, E. L., Woolfenden, A. E., Lawrence, S.,
Babar, I., Vogel, S., Crowley, D., Bronson, R. T. and Jacks, T.
(2005). Identification of bronchioalveolar stem cells in normal
lung and lung cancer. Cell
121,823
-835.[CrossRef][Medline]
Kotton, D. N., Ma, B. Y., Cardoso, W. V., Sanderson, E. A.,
Summer, R. S., Williams, M. C. and Fine, A. (2001).
Bone marrow-derived cells as progenitors of lung alveolar epithelium.
Development 128,5181
-5188.[Medline]
Krause, D. S., Theise, N. D., Collector, M. I., Henegariu, O.,
Hwang, S., Gardner, R., Neutzel, S. and Sharkis, S. J.
(2001). Multi-organ, multi-lineage engraftment by a single bone
marrow-derived stem cell. Cell
105,369
-377.[CrossRef][Medline]
Kurita, T., Medina, R. T., Mills, A. A. and Cunha, G. R.
(2004). Role of p63 and basal cells in the prostate.
Development 131,4955
-4964.
Lammert, E., Cleaver, O. and Melton, D. (2003).
Role of endothelial cells in early pancreas and liver development.
Mech. Dev. 120,59
-64.[CrossRef][Medline]
Lanza, R. (2006). Essentials of Stem
Cell Biology. New York: Academic Press.
Lawson, G. W., Van Winkle, L. S., Toskala, E., Senior, R. M.,
Parks, W. C. and Plopper, C. G. (2002). Mouse strain
modulates the role of the ciliated cell in acute tracheobronchial airway
injury-distal airways. Am. J. Pathol.
160,315
-327.
Levine, M. and Davidson, E. H. (2005). Gene
regulatory networks for development. Proc. Natl. Acad. Sci.
USA 102,4936
-4942.
Li, J., Tzu, J., Chen, Y., Zhang, Y. P., Nguyen, N. T., Gao, J.,
Bradley, M., Keene, D. R., Oro, A. E., Miner, J. H. et al.
(2003). Laminin-10 is crucial for hair morphogenesis.
EMBO J. 22,2400
-2410.[CrossRef][Medline]
Lie, D. C., Colamarino, S. A., Song, H. J., Desire, L., Mira,
H., Consiglio, A., Lein, E. S., Jessberger, S., Lansford, H., Dearie,
A. R. et al. (2005). Wnt signalling regulates adult
hippocampal neurogenesis. Nature
437,1370
-1375.[CrossRef][Medline]
Liu, J. Y., Nettesheim, P. and Randell, S. H.
(1994). Growth and differentiation of tracheal epithelial
progenitor cells. Am. J. Physiol.
266,L296
-L307.[Medline]
Macpherson, H., Keir, P., Webb, S., Samuel, K., Boyle, S.,
Bickmore, W., Forrester, L. and Dorin, J. (2005). Bone
marrow-derived SP cells can contribute to the respiratory tract of mice in
vivo. J. Cell Sci. 118,2441
-2450.
Matsumoto, K., Yoshitomi, H., Rossant, J. and Zaret, K. S.
(2001). Liver organogenesis promoted by endothelial cells prior
to vascular function. Science
294,559
-563.
Metzger, D. and Chambon, P. (2001). Site- and
time-specific gene targeting in the mouse. Methods
24, 71-80.[CrossRef][Medline]
Nguyen, N. M., Kelley, D. G., Schlueter, J. A., Meyer, M. J.,
Senior, R. M. and Miner, J. H. (2005). Epithelial laminin
alpha5 is necessary for distal epithelial cell maturation, VEGF production,
and alveolization in the developing murine lung. Dev.
Biol. 282,111
-125.[CrossRef][Medline]
Ortiz, L. A., Gambelli, F., McBride, C., Gaupp, D., Baddoo, M.,
Kaminski, N. and Phinney, D. G. (2003). Mesenchymal stem cell
engraftment in lung is enhanced in response to bleomycin exposure and
ameliorates its fibrotic effects. Proc. Natl. Acad. Sci.
USA 100,8407
-8411.
Overturf, K., Al-Dhalimy, M., Finegold, M. and Grompe, M.
(1999). The repopulation potential of hepatocyte populations
differing in size and prior mitotic expansion. Am. J.
Pathol. 155,2135
-2143.
Pack, R. J., Al-Ugaily, L. H. and Morris, G.
(1981). The cells of the tracheobronchial epithelium of the
mouse: a quantitative light and electron microscope study. J.
Anat. 132,71
-84.[Medline]
Paris, F., Fuks, Z., Kang, A., Capodieci, P., Juan, G.,
Ehleiter, D., Haimovitz-Friedman, A., Cordon-Cardo, C. and Kolesnick, R.
(2001). Endothelial apoptosis as the primary lesion initiating
intestinal radiation damage in mice. Science
293,293
-297.
Park, K. S., Wells, J. M., Zorn, A. M., Wert, S. E., Laubach, V.
E., Fernandez, L. G. and Whitsett, J. A. (2005).
Transdifferentiation of ciliated cells during repair of the respiratory
epithelium. Am. J. Respir. Cell Mol. Biol.
34,151
-157.
Pearton, D. J., Yang, Y. and Dhouailly, D.
(2005). Transdifferentiation of corneal epithelium into epidermis
occurs by means of a multistep process triggered by dermal developmental
signals. Proc. Natl. Acad. Sci. USA
102,3714
-3719.
Plopper, C. G., Suverkropp, C., Morin, D., Nishio, S. and
Buckpitt, A. (1992). Relationship of cytochrome P-450
activity to Clara cell cytotoxicity. I. Histopathologic comparison of the
respiratory tract of mice, rats and hamsters after parenteral administration
of naphthalene. J. Pharmacol. Exp. Ther.
261,353
-363.
Potten, C. S. (2004). Development of epithelial
stem cell concepts. In Handbook of Stem Cells: Vol. 2 Adult and
Fetal Stems Cell (ed. R. Lanza), pp.1
-12. New York: Academic Press.
Pull, S. L., Doherty, J. M., Mills, J. C., Gordon, J. I. and
Stappenbeck, T. S. (2005). Activated macrophages are an
adaptive element of the colonic epithelial progenitor niche necessary for
regenerative responses to injury. Proc. Natl. Acad. Sci.
USA 102,99
-104.
Raff, M. (2003). Adult stem cell plasticity:
fact or artifact? Annu. Rev. Cell Dev. Biol.
19, 1-22.[CrossRef][Medline]
Ramalho-Santos, M., Yoon, S., Matsuzaki, Y., Mulligan, R. C. and
Melton, D. A. (2002). `Stemness': transcriptional profiling
of embryonic and adult stem cells. Science
298,597
-600.
Rawlins, E. L. and Hogan, B. L. (2005).
Intercellular growth factor signaling and the development of mouse tracheal
submucosal glands. Dev. Dyn.
233,1378
-1385.[CrossRef][Medline]
Reader, J. R., Tepper, J. S., Schelegle, E. S., Aldrich, M. C.,
Putney, L. F., Pfeiffer, J. W. and Hyde, D. M. (2003).
Pathogenesis of mucous cell metaplasia in a murine asthma model.
Am. J. Pathol. 162,2069
-2078.
Rendl, M., Lewis, L. and Fuchs, E. (2005).
Molecular dissection of mesenchymal-epithelial interactions in the hair
follicle. PLoS Biol. 3,e331
.[CrossRef][Medline]
Reynolds, S. D., Giangreco, A., Power, J. H. and Stripp, B.
R. (2000a). Neuroepithelial bodies of pulmonary airways serve
as a reservoir of progenitor cells capable of epithelial regeneration.
Am. J. Pathol. 156,269
-278.
Reynolds, S. D., Hong, K. U., Giangreco, A., Mango, G. W.,
Guron, C., Morimoto, Y. and Stripp, B. R. (2000b).
Conditional clara cell ablation reveals a self-renewing progenitor function of
pulmonary neuroendocrine cells. Am. J. Physiol. Lung Cell Mol.
Physiol. 278,L1256
-L1263.
Reynolds, S. D., Reynolds, P. R., Pryhuber, G. S., Finder, J. D.
and Stripp, B. S. (2002). Secretoglobins SCGB3A1 and SCGB3A2
define secretory cell subsets in mouse and human airways. Am. J.
Respir. Crit. Care Med. 166,1498
-1509.
Rojas, M., Xu, J., Woods, C. R., Mora, A. L., Spears, W., Roman,
J. and Brigham, K. L. (2005). Bone marrow-derived
mesenchymal stem cells in repair of the injured lung. Am. J.
Respir. Cell Mol. Biol. 33,145
-152.
Schoch, K. G., Lori, A., Burns, K. A., Eldred, T., Olsen, J. C.
and Randell, S. H. (2004). A subset of mouse tracheal
epithelial basal cells generates large colonies in vitro. Am. J.
Physiol. Lung Cell Mol. Physiol.
286,L631
-L642.
Shackleton, M., Vaillant, F., Simpson, K. J., Stingl, J., Smyth,
G. K., Asselin-Labat, M. L., Wu, L., Lindeman, G. J. and Visvader, J. E.
(2006). Generation of a functional mammary gland from a single
stem cell. Nature 439,84
-88.[CrossRef][Medline]
Shen, Q., Goderie, S. K., Jin, L., Karanth, N., Sun, Y.,
Abramova, N., Vincent, P., Pumiglia, K. and Temple, S.
(2004). Endothelial cells stimulate self-renewal and expand
neurogenesis of neural stem cells. Science
304,1338
-1340.
Shu, W., Guttentag, S., Wang, Z., Andl, T., Ballard, P., Lu, M.
M., Piccolo, S., Birchmeier, W., Whitsett, J. A., Millar, S. E. et al.
(2005). Wnt/beta-catenin signaling acts upstream of N-myc, BMP4,
and FGF signaling to regulate proximal-distal patterning in the lung.
Dev. Biol. 283,226
-239.[CrossRef][Medline]
Signoretti, S., Pires, M. M., Lindauer, M., Horner, J. W.,
Grisanzio, C., Dhar, S., Majumder, P., McKeon, F., Kantoff, P. W., Sellers, W.
R. et al. (2005). p63 regulates commitment to the prostate
cell lineage. Proc. Natl. Acad. Sci. USA
102,11355
-11360.
Stevens, T. P., McBride, J. T., Peake, J. L., Pinkerton, K. E.
and Stripp, B. R. (1997). Cell proliferation contributes to
PNEC hyperplasia after acute airway injury. Am. J.
Physiol. 272,L486
-L493.[Medline]
Stripp, B. R., Maxson, K., Mera, R. and Singh, G.
(1995). Plasticity of airway cell proliferation and gene
expression after acute naphthalene injury. Am. J.
Physiol. 269,L791
-L799.[Medline]
Theise, N. D., Henegariu, O., Grove, J., Jagirdar, J., Kao, P.
N., Crawford, J. M., Badve, S., Saxena, R. and Krause, D. S.
(2002). Radiation pneumonitis in mice: a severe injury model for
pneumocyte engraftment from bone marrow. Exp. Hematol.
30,1333
-1338.[CrossRef][Medline]
Thurlbeck, W. M. (1975). Lung growth and
alveolar multiplication. Pathobiol. Annu.
5, 1-34.[Medline]
Tumbar, T., Guasch, G., Greco, V., Blanpain, C., Lowry, W. E.,
Rendl, M. and Fuchs, E. (2004). Defining the epithelial stem
cell niche in skin. Science
303,359
-363.
Tyner, J. W., Kim, E. Y., Ide, K., Pelletier, M. R., Roswit, W.
T., Morton, J. D., Battaile, J. T., Patel, A. C., Patterson, G. A., Castro, M.
et al. (2006). Blocking airway mucous cell metaplasia by
inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals.
J. Clin. Invest. 116,309
-321.[CrossRef][Medline]
Van Winkle, L. S., Buckpitt, A. R., Nishio, S. J., Isaac, J. M.
and Plopper, C. G. (1995). Cellular response in
naphthalene-induced Clara cell injury and bronchiolar epithelial repair in
mice. Am. J. Physiol.
269,L800
-L818.[Medline]
Van Winkle, L. S., Johnson, Z. A., Nishio, S. J., Brown, C. D.
and Plopper, C. G. (1999). Early events in
naphthalene-induced acute Clara cell toxicity: comparison of membrane
permeability and ultrastructure. Am. J. Respir. Cell Mol.
Biol. 21,44
-53.
Vu, T. H., Alemayehu, Y. and Werb, Z. (2003).
New insights into saccular development and vascular formation in lung
allografts under the renal capsule. Mech. Dev.
120,305
-313.[CrossRef][Medline]
Watkins, D. N., Berman, D. M., Burkholder, S. G., Wang, B.,
Beachy, P. A. and Baylin, S. B. (2003). Hedgehog signalling
within airway epithelial progenitors and in small-cell lung cancer.
Nature 422,313
-317.[CrossRef][Medline]
Watt, F. M. and Hogan, B. L. M. (2000). Out of
Eden: stem cells and their niches. Science
287,1427
-1430.
Weaver, M., Dunn, N. R. and Hogan, B. L.
(2000). Bmp4 and Fgf10 play opposing roles during lung bud
morphogenesis. Development
127,2695
-2704.[Abstract]
Weaver, M., Batts, L. and Hogan, B. L. (2003).
Tissue interactions pattern the mesenchyme of the embryonic mouse lung.
Dev. Biol. 258,169
-184.[CrossRef][Medline]
Wells, A. B. (1970). The kinetics of cell
proliferation in the tracheobronchial epithelia of rats with and without
chronic respiratory disease. Cell Tissue Kinet.
3, 185-206.[Medline]
Williams, O. W., Sharafkhaneh, A., Kim, V., Dickey, B. F. and
Evans, C. M. (2006). Airway mucus: from production to
secretion. Am. J. Respir. Cell Mol. Biol.
34,527
-536.
Xin, L., Ide, H., Kim, Y., Dubey, P. and Witte, O. N.
(2003). In vivo regeneration of murine prostate from dissociated
cell populations of postnatal epithelia and urogenital sinus mesenchyme.
Proc. Natl. Acad. Sci. USA
100,11896
-11903.
Xin, L., Lawson, D. A. and Witte, O. N. (2005).
The Sca-1 cell surface marker enriches for a prostate-regenerating cell
subpopulation that can initiate prostate tumorigenesis. Proc. Natl.
Acad. Sci. USA 102,6942
-6947.
Yoshitomi, H. and Zaret, K. S. (2004).
Endothelial cell interactions initiate dorsal pancreas development by
selectively inducing the transcription factor Ptf1a.
Development 131,807
-817.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  T. van Haaften, R. Byrne, S. Bonnet, G. Y. Rochefort, J. Akabutu, M. Bouchentouf, G. J. Rey-Parra, J. Galipeau, A. Haromy, F. Eaton, et al. Airway Delivery of Mesenchymal Stem Cells Prevents Arrested Alveolar Growth in Neonatal Lung Injury in Rats Am. J. Respir. Crit. Care Med., December 1, 2009; 180(11): 1131 - 1142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.-N. Tsao, M. Vasconcelos, K. I. Izvolsky, J. Qian, J. Lu, and W. V. Cardoso Notch signaling controls the balance of ciliated and secretory cell fates in developing airways Development, July 1, 2009; 136(13): 2297 - 2307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Guseh, S. A. Bores, B. Z. Stanger, Q. Zhou, W. J. Anderson, D. A. Melton, and J. Rajagopal Notch signaling promotes airway mucous metaplasia and inhibits alveolar development Development, May 15, 2009; 136(10): 1751 - 1759. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lee, R. Reddy, L. Barsky, J. Scholes, H. Chen, W. Shi, and B. Driscoll Lung alveolar integrity is compromised by telomere shortening in telomerase-null mice Am J Physiol Lung Cell Mol Physiol, January 1, 2009; 296(1): L57 - L70. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E.L. Rawlins, T. Okubo, J. Que, Y. Xue, C. Clark, X. Luo, and B.L.M. Hogan Epithelial Stem/Progenitor Cells in Lung Postnatal Growth, Maintenance, and Repair Cold Spring Harb Symp Quant Biol, November 26, 2008; (2008) sqb.2008.73.037v2. [Abstract] [PDF]
|
|
|
|
|
|
D.M. Raiser, S.J. Zacharek, R.R. Roach, S.J. Curtis, K.W. Sinkevicius, D.W. Gludish, and C.F. Kim Stem Cell Biology in the Lung and Lung Cancers: Employing Pulmonary Context and Classic Approaches Cold Spring Harb Symp Quant Biol, November 26, 2008; (2008) sqb.2008.73.036v2. [Abstract] [PDF]
|
|
|
|
 |
|
 W. V. Cardoso and J. A. Whitsett Resident Cellular Components of the Lung: Developmental Aspects Proceedings of the ATS, September 15, 2008; 5(7): 767 - 771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. G. Crystal, S. H. Randell, J. F. Engelhardt, J. Voynow, and M. E. Sunday Airway Epithelial Cells: Current Concepts and Challenges Proceedings of the ATS, September 15, 2008; 5(7): 772 - 777. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Weaver and M. A. Krasnow Dual Origin of Tissue-Specific Progenitor Cells in Drosophila Tracheal Remodeling Science, September 12, 2008; 321(5895): 1496 - 1499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Dovey, S. J. Zacharek, C. F. Kim, and J. A. Lees Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion PNAS, August 19, 2008; 105(33): 11857 - 11862. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Rawlins Lung Epithelial Progenitor Cells: Lessons from Development Proceedings of the ATS, August 15, 2008; 5(6): 675 - 681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Warburton, L. Perin, R. DeFilippo, S. Bellusci, W. Shi, and B. Driscoll Stem/Progenitor Cells in Lung Development, Injury Repair, and Regeneration Proceedings of the ATS, August 15, 2008; 5(6): 703 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Weiss, J. K. Kolls, L. A. Ortiz, A. Panoskaltsis-Mortari, and D. J. Prockop Stem Cells and Cell Therapies in Lung Biology and Lung Diseases Proceedings of the ATS, July 15, 2008; 5(5): 637 - 667. [Full Text] [PDF]
|
|
|
|
|
|
E. L. Rawlins and B. L. M. Hogan Ciliated epithelial cell lifespan in the mouse trachea and lung Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L231 - L234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kida, M. L. Mucenski, A. R. Thitoff, T. D. Le Cras, K.-S. Park, M. Ikegami, W. Muller, and J. A. Whitsett GP130-STAT3 Regulates Epithelial Cell Migration and Is Required for Repair of the Bronchiolar Epithelium Am. J. Pathol., June 1, 2008; 172(6): 1542 - 1554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Jakiela, R. Brockman-Schneider, S. Amineva, W.-M. Lee, and J. E. Gern Basal Cells of Differentiated Bronchial Epithelium Are More Susceptible to Rhinovirus Infection Am. J. Respir. Cell Mol. Biol., May 1, 2008; 38(5): 517 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rajagopal, T. J. Carroll, J. S. Guseh, S. A. Bores, L. J. Blank, W. J. Anderson, J. Yu, Q. Zhou, A. P. McMahon, and D. A. Melton Wnt7b stimulates embryonic lung growth by coordinately increasing the replication of epithelium and mesenchyme Development, May 1, 2008; 135(9): 1625 - 1634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Gleiberman, T. Michurina, J. M. Encinas, J. L. Roig, P. Krasnov, F. Balordi, G. Fishell, M. G. Rosenfeld, and G. Enikolopov Genetic approaches identify adult pituitary stem cells PNAS, April 29, 2008; 105(17): 6332 - 6337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. F. Kim Paving the road for lung stem cell biology: bronchioalveolar stem cells and other putative distal lung stem cells Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1092 - L1098. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Giangreco, K. R. Groot, and S. M. Janes Lung Cancer and Lung Stem Cells: Strange Bedfellows? Am. J. Respir. Crit. Care Med., March 15, 2007; 175(6): 547 - 553. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Rawlins, L. E. Ostrowski, S. H. Randell, and B. L. M. Hogan Inaugural Article: Lung development and repair: Contribution of the ciliated lineage PNAS, January 9, 2007; 104(2): 410 - 417. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Randell Airway Epithelial Stem Cells and the Pathophysiology of Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2006; 3(8): 718 - 725. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
