Department of Biological Sciences, South Road, University of Durham, Durham DH1 3LE, UK
* Authors for correspondence (e-mail: colin.jahoda{at}durham.ac.uk; nicholas.hole{at}durham.ac.uk)
Accepted 15 May 2002
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Summary |
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Key words: Hair follicle, Dermal papilla, Dermal sheath, Haematopoietic stem cell
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Introduction |
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However, if the plasticity of stem cells is ever to be used in
therapeutics, ease of access to stem cell repositories will be very important
and the provision of mesenchymal stem cells from bone marrow requires bone
marrow extraction and cell sorting. Several research groups have investigated
alternative sources of adult stem cells. Adipocytes obtained from subcutaneous
fat by liposuction have been shown to produce osteogenic, chondrogenic and
myogenic derivatives (Zuk et al.,
2001), but no blood or nerve cells. Stem cells obtained from skin
dermis can produce neural as well as mesodermal derivatives
(Toma et al., 2001
), but the
origin of this stem cell population is unclear, as the initial dermal
population is heterogeneous. However, cells of the hair follicle are highly
accessible and can also be isolated as discrete populations.
Unlike some of the cell types whose stem cell potential is being
investigated, hair follicle dermal cells derive from an organ that is unique
in the adult mammal in terms of its range of developmental activities. There
is increasing evidence that follicles contain stem cells that play key roles
for skin as a whole, and within the follicle, the lineage relationships
between the dermal cell populations is well defined
(Taylor et al., 2000;
Oshima et al., 2001
). Hair
follicle dermal cells are perhaps best considered as embryonic type cells
retained in an adult system, and flexible in their range of activities, rather
than specialised adult stem cells. The embryonic-like properties of the hair
follicle dermal cells derive from the fact that they segregate from
intrafollicular dermis relatively early on in follicle development and assume
characteristic morphological and molecular phenotypes. Experimentally we have
shown that adult hair follicle dermal cells have unparalleled capacity to
induce hair growth when combined with different epidermal partners
(Jahoda and Reynolds, 1996
).
Recently we transplanted follicle dermal sheath tissue from one person to
another and showed that it induced follicles that grew hair without undergoing
the rejection process normally associated with allografts
(Reynolds et al., 1999
).
Therefore dermal sheath cells would appear to possess a degree of
immunoprivilege that underlines their potential for use as universal donors in
stem cell-based therapies. When the hair follicle base is experimentally
amputated, residual cells of the dermal sheath (DS;
Fig. 1) replace the main
inductive dermal element the dermal papilla (DP), and restore hair growth in a
unique example of mammalian regeneration. Thus there is also clear mesenchymal
cell lineage transition from DS to DP cells, in this case (apparently)
mediated by the follicle epithelium
(Reynolds and Jahoda,
1996
).
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Materials and Methods |
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Establishment and maintenance of DP and DS cell cultures
Cell culture was performed as previously described
(Jahoda and Oliver, 1981).
Around a dozen papillae, or pieces of sheath tissue were pooled and cultured
in 35 mm Petri dishes. All explants were initially maintained in MEM
supplemented with 20% fetal calf serum (FCS, Gibco BRL; Renfrew, UK) at
37°C, 5% CO2. The cultures were routinely passaged as described
elsewhere (Reynolds and Jahoda,
1991
).
Colony forming unit (CFU) assays
CFU-GEMM assay
CFU-GEMM assays were performed according to the manufacturer's instructions
(Stem Cell Technologies; Vancouver, Canada), In brief, 3x104
cells in a total volume of 0.3 ml were added to 3 ml of Methocult medium
yielding triplicate cultures of 1.1 ml each. Methocult containing cells was
dispensed into three 35 mm dishes using a 16G blunt-end needle. Two plates
were then placed into a 100 mm covered dish containing a third uncovered dish
containing 3 ml of sterile water. Cultures were then placed in a 37°C
incubator maintained with 5% CO2 and >95% humidity. The
concentration of cytokines in Methocult is as follows: IL-3 (10 ng/ml); IL-6
(10 ng/ml), SCF (50 ng/ml), Epo (3 units/ml). Dissected parts from the hair
follicle were placed on top of methocult (7-8 in total) and plates were
incubated as above.
CFU-A assay
The in vitro CFU-A assay was set up as described previously
(Pragnell et al., 1988). In
brief, a feeder layer consisting of 0.6% agar in a modified Eagle's medium
(
-MEM; Gibco BRL) with conditioned medium from two cell lines (AF1-19T,
a source of granulocyte macrophage colony stimulating factor, GM-CSF; and
L929, a source of M-CSF) was poured into 3 cm diameter tissue culture grade
dishes (1 ml per layer). Dissected DP and DS (5-6 per plate) were placed on
top of the 0.3% agar and
-MEM mixture to form the upper layer. When DP
or DS cells were assayed, 3x104 cells were added to 0.3% agar
in
-MEM and plated to form an upper layer. The dishes were incubated
for 11 days at 37°C in a humidified atmosphere with 5% O2 and
10% CO2. The presence or absence of haematopoietic progeny was
determined by the formation of mixed colonies of neutrophils and macrophages
with diameters greater than 2 mm after 11 days of incubation. The mixed nature
of the developing colonies and the high proliferative capacity of the
clonogenic cell, alongside data on radiation sensitivity, anatomical location
and sensitivity to mitotic poison indicates that this assay detects a
primitive haematopoietic cell analogous to CFU-S
(Pragnell et al., 1988
;
Graham et al., 1990
).
Stem cell transplantation
DP and DS cells from Zin40 mice cultured as described above were harvested
by trypsinisation. 20,000 cells were mixed with 200,000 nucleated bone marrow
cells from Balb/c mice and injected intravenously into recipient Balb/c mice
that had received 1.2 Gy of -irradiation. Recipients received
prophylactic aureomycin in drinking water. For transplantation into secondary
recipients, bone marrow was harvested from the primary mice and
2x106 nucleated cells were injected into each secondary
Balb/c recipient, prepared as described above.
Analysis of transplant recipients
Bone marrow, spleen and peripheral blood were collected from both primary
and secondary sacrificed recipients and DNA was extracted using the Wizard
Genomic DNA Purification Kit (Promega, Southampton, UK). Thirty five cycles of
94°C (1 minute), 62°C (1 minute) and 72°C (1 minute) were used to
amplify lacZ from 100 ng of genomic DNA with the following primer pair:
5'-CGCTCACATTTAATGTTGATGAAAGC and 5'-TCCAGATAACTGCCGTCACTCCAA. A
second PCR was performed with murine Wnt8b specific primers
5'-AACGTGGGCTTCGGAGAGGC and 5'-GCCCGCGCCCTGCAGCAGGT as an internal
control.
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Results |
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We then established primary explant cultures of DS and DP cells and carried out CFU-A assays on cells passaged from 1 to 3 times (Fig. 4A,B). Both DS and DP cell cultures displayed haematopoietic activity as shown by the production of large haematopoietic colonies in CFU-A assays that were indistinguishable from those formed by conventional bone-marrow-derived progenitors (Fig. 4C,D). Flow cytometry of the DP or DS cultures with anti-CD45 monoclonal antibody (PharMingen, San Diego, CA) was unable to detect pre-formed haematopoietic cells at this level of analysis; however, CD45 cells were detected in the colonies formed in the CFU-A assays. Coupled with the comparatively small number of haematopoietic colonies formed (approximately 1 in 6000 DP or DS cells plated in CFU assay), these data suggest that if pre-formed haematopoietic progenitors are present there must be only relatively small numbers in each follicle.
|
Although the CFU data we obtained from both the dissected DP and DS and
their respective cultures strongly suggested the presence of primitive
haematopoietic potential, these in vitro assays detect haematopoietic
progenitors that include, but are not exclusively, HSC. To determine the
presence of HSC activity in these cultures, we assessed their capacity to
generate long-term multi-lineage haematopoietic reconstitution of myeloablated
recipient animals. For this we used a competitive repopulation transplantation
assay (Harrison, 1980), in
which a given cell population is required to compete in the same recipient
with a genetically distinguishable standard source of haematopoietic stem cell
activity. Nucleated cells from unfractionated bone marrow of Balb/c mice
(2x105 cells per animal) and cultured DS or DP cells from
Zin40 mice (2x104 cells per animal) were injected
intravenously into lethally irradiated Balb/c recipients. Zin40 mice were used
as the source of donor tissue because they carry a transgene (LacZ); thus
cells derived from the hair follicle could be distinguished from host or
carrier bone marrow by genotype. Analysis using PCR is preferable to flow
cytometry studies using fluororescein di-galactoside since our experience has
shown high background staining of mouse tissues using this technique. Between
4 and 5 months post-irradiation we sacrificed eight transplanted mice and
extracted DNA from the spleen, bone marrow and peripheral blood. PCR analysis
for lacZ indicated the presence of dermal-derived cells in the recipient
peripheral blood, spleen and bone marrow
(Fig. 5A;
Table 2). A semi-quantitative
analysis of lacZ detection using variable percentages of transgenic and
wild-type splenocytes show that this assay can detect low percentages of
lacZ-labelled cells against a wild-type background
(Fig. 5C). We sacrificed one
recipient mouse 13 months after transplantation and found the presence of
dermal-derived cells in the peripheral blood, spleen and bone marrow. We also
sorted splenocytes from the recipient females into different subpopulations
(e.g. B cells, T cells, myeloid cells) using immunomagnetic cell sorting
(Miltenyi Biotech) and examined each for the presence of the transgene.
Dermal-derived cells were found to have contributed to all haematopoietic
lineages studied (Fig. 5B). The
proportion of clonogenic haematopoietic precursors that were derived from the
transgenic dermal cultures was then assessed by limiting dilution CFU-A
analysis of recipient bone marrow. In three recipients that had received a
mixture of DP and bone marrow cells, 72%, 73% and 75% of colonies formed from
their bone marrow were found to be transgenic by PCR. Similarly, with two
recipients that had received a mixture of DS and bone marrow cells, 80% and
77% of the colonies were transgenic. Although in our opinion this is strong
evidence that cells of the DP and DS contain HSC activity, we then tested this
further by transplanting bone marrow from the primary recipients into
myeloablated secondary recipients as a robust test of stem cell competence.
PCR analysis of the peripheral blood, spleen and bone marrow of these
secondary mice 8 weeks post-irradiation indicated the presence of
dermal-derived cells (Table 2).
We have also found transgenic haematopoietic cells in all leukocyte
populations that have been tested from these secondary recipients. Moreover,
PCR analysis on single CFU-A colonies from the bone marrow of two secondary
mice showed that 58% and 77% of colonies respectively were lacZ positive.
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Discussion |
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The hair follicle has been shown to be associated with differentiated blood
cells in situ such as CD4+ and CD8+ T cells, Langerhans
cells, macrophages and mast cells
(Christoph et al., 2000). It is
also vascularised so there is a finite possibility that what we observed was
due to the presence of haematopoietic stem cells carried in the peripheral
blood or, potentially, recruited from the endothelial cells themselves. To
address this, we investigated the haematopoietic potential of aorta and
peripheral blood and they both failed to show haematopoietic activity in our
in vitro assays. In view of this data and the high proportion of follicles
demonstrating haematopoietic activity it is likely that what we have seen with
the hair-follicle-derived cells is a product of endogenous activity for which
there are at least three possible explanations, none of which can be entirely
excluded. One is that the apparently lineage-restricted dermal cells undergo a
general reprogramming, possibly via extracellular cues from the new
microenvironment into which they are introduced. There are many recent reports
involving adult cell populations once considered to be lineage restricted,
showing greater differentiation plasticity, several of which have involved
haematopoietic stem cell activity (Jackson
et al., 1999
; Gussoni et al.,
1999
; Bjornson et al.,
1999
). Our current observations tend to argue against a general
reprogramming event. Although nearly all follicles demonstrated endogenous
haematopoietic activity, the fact that 1 in 6000 of cultured cells plated in
the CFU experiments had haematopoietic potential suggests that these cells may
be quite rare within each follicle. In spite of this, the dermal cultures
appear to be at least as potent as conventional bone marrow, the high
percentage of follicle-derived clonogenic cells in recipient animals
suggesting, indeed, that these cell types may be capable of out-competing
conventional bone marrow HSC. This result is similar to that found in work
with stem cells obtained from skeletal muscle
(Jackson et al., 1999
).
Another alternative is that follicles contain a small resident population of
haematopoietic stem cells. Although we are confident that the
follicle-associated HSC activity is not a consequence of residual peripheral
blood within the dermal structures, we cannot exclude the possibility that the
activity is a result of prior HSC recruitment from conventional haematopoietic
sites. In this context, a recent report has shown that adult muscle-derived
haematopoietic stem cell activity emanates from cells that are haematopoietic
in origin (McKinney-Freeman et al.,
2002
). Our current work is aimed at distinguishing this
possibility from the first one, and from the third option, which is that there
are small numbers of permissive stem cells resident in the hair follicle
dermis that possess multi-potency. In this context a single
bone-marrow-derived stem cell has been shown to contribute to a number of
different organ systems (Krause et al.,
2001
). Moreover, it was recently reported
(Toma et al., 2001
) that stem
cells derived from skin dermis could be grown and differentiated in culture to
produce multiple differentiation products including neurons and glia. This
work suggests that there may be a multipotent stem cell present in the dermis
of skin whose origin is unknown. Within skin, the hair follicle is seen as
providing a discrete well-protected niche, and the follicle epithelium has
recently been the focus of much skin stem cell and tumor biology research
(Taylor et al., 2000
;
Oshima et al., 2001
;
Jahoda and Reynolds, 2000
). In
the current work we found no evidence of haematopoietic activity from
epithelial tissue isolated from the lower follicle. Moreover, the sections of
follicle above the base, which incorporate the main epithelial stem cell
compartments including the bulge region, revealed a reduced haematopoietic
response compared with the end bulb. This highlights the follicle dermis as a
separate location for progenitor activity. In a recent paper we suggested
that, just as follicle epithelial cells are a major stem cell source for skin
epidermis in wound healing, so follicle dermal cells might play the equivalent
role in replacing dermal cells in dermal repair
(Jahoda and Reynolds, 2001
).
In the light of recent evidence that follicle epithelial stem cells are
involved in the continuous physiological process of replacement of epidermis
in normal healthy skin (Taylor et al.,
2000
), we also hypothesised that follicle dermal cells might be
involved in regulating the cellularity of normal dermis. The haematopoietic
activity evident in the current study now gives rise to the idea that, within
skin, the protected environment of the hair follicle is a key repository for a
broad range of stem cell activities. In this context it is interesting that in
the paper describing neuronal cell differentiation from skin dermis
(Toma et al., 2001
), all the
skin used for the experiments contained hair follicles.
Our observation that hair follicles possess cells with endogenous
haematopoietic activity could have considerable dermatological significance.
There is growing interest in hair follicle immunology and evidence that the
follicle has a unique immunological profile
(Paus et al., 1999;
Gilliam et al., 1998
;
Westgate et al., 1991
).
Therefore, it is possible to envisage that the capacity to produce
haematopoietic cells locally in skin could play a role in, for example, wound
healing and immune surveillance. This might be true, especially in view of the
recent reports that the hair follicle can serve as an immediate reservoir of
Langerhans cells between bone marrow and epidermis
(Gilliam et al., 1998
). By
contrast, if it turns out that the follicle harbors a few multi-potent stem
cells, then the effects that we have observed could be just a manifestation of
the different environmental conditions that these cells are being put into. In
any event, this does not detract from the essential fact that
hair-follicle-derived cells can be turned into blood for practical
purposes.
The implications for such new sources of HSC for potential therapy have
been highlighted elsewhere (Saba et al.,
2000). However, follicle-derived HSC activity may be of particular
relevance to the human condition. It is now well established that rodent hair
follicles display immune privilege, and our work and that of others has
indicated that this is true for human dermal sheath cells
(Paus et al., 1999
;
Reynolds et al., 1999
); such
cells may therefore prove to be admirable donor cell types in stem-cell-based
therapies. Further, the ability to readily access dermal cell populations by
skin biopsy, rather than a potentially more invasive procedure required for
other stem cell types may make them particularly appropriate as a source of
autologous or allogeneic HSC activity.
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Acknowledgments |
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Footnotes |
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Recent observations indicate that some haematopoietic activity may not be seen under in vitro culture conditions that promote hair growth in vitro.
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