1 Department of Immunology, Graduate School of Pharmaceutical Sciences, Osaka
University, Suita, Osaka 565-0871, Japan
2 Department of Molecular Therapy, National Institute of Neuroscience, National
Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan
3 Division of Oncogenesis, Biomedical Research Center, Osaka University Graduate
School of Medicine, Suita, Osaka 565-0871, Japan
* Author for correspondence (e-mail: hiroshiy{at}phs.osaka-u.ac.jp )
Accepted 19 December 2001
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Summary |
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Key words: Muscle regeneration, Transplantation, Satellite cell
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Introduction |
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Wakitani et al. (Wakitani et al.,
1995) were the first to show that mesenchymal stem cells from rat
bone marrow have the ability to differentiate into myotubes when they are
cultured in the presence of 5-azacytidine. In vivo transplantation of such
cells into the muscles of X-chromosome-linked muscular dystrophy
(mdx) mice induces dystrophin-positive muscle fibres
(Saito et al., 1995
). These
results prompted investigators to speculate that the transplanted bone marrow
cells can move into damaged muscle and grow into new muscle fibres in mice
(for a review, see Cossu and Mavilio,
2000
). This also has clinical implications, not only for muscular
dystrophy but also for various tissue-specific hereditary disorders. Recently,
several investigators have reported that transplanted bone marrow cells
participate in the muscle regeneration process in irradiated recipient mice
(Ferrari et al., 1998
;
Gussoni et al., 1999
;
Bittner et al., 1999
). In these
studies, bone marrow cells were distinguished from recipient cells by
donor-specific gene expression signals such as nuclear ß-galactosidase or
the presence of a Y chromosome. However, muscle fibres containing
donor-cell-derived chromosomes never exceeded 1% of the total fibres in an
average muscle.
It is widely accepted that postnatal growth and repair of skeletal muscle
are normally mediated by the satellite cells that surround muscle fibres.
Satellite cells are mononucleate precursor cells that are located beneath the
basal lamina and sarcolemma of myofibres
(Mauro, 1961) (for reviews,
see Bischoff, 1994
;
Cullen, 1997
). Satellite cells
first appear in the limbs of mouse embryos between embryonic day 16 and 18,
and the cell number reaches a peak in neonatal mice. In adult mice, less than
5% of the total nuclei are satellite cells, and this gradually declines with
age (Cossu et al., 1983
) (for
reviews, see Campion, 1984
;
Mazanet and Franzini-Armstrong,
1986
; Bischoff,
1994
). In chicken, satellite cells appear during late
embryogenesis (Hartley et al.,
1992
). Adult bone marrow contains mesenchymal stem cells from
which muscle precursor cells can be supplied; however, there is no definitive
evidence as to whether or not satellite cells are recruited from bone marrow
to muscle under physiological or pathological conditions. Moreover, it has not
yet been clarified whether the bone-marrow-derived cells exist as satellite
cells in the radiation chimera experiments.
In this report we demonstrate that the injection of bone marrow or fetal liver cells from EGFP-transgenic (GFP-Tg) mice into neonatal mice establishes tolerance to allogeneic donor cells, and the muscle-reconstituting efficiencies of these two cell populations were compared. Moreover, we provide the first report that neonatally injected cells are recruited to the muscle, where they probably reside as satellite cells, and participate in normal muscle development. The combined procedure neonatal tolerance induction with cells from GFP-Tg mice is a useful strategy for further studies of satellite cell recruitment and muscle regeneration.
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Materials and Methods |
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Bone marrow or fetal liver cell reconstitution
Bone marrow chimeras were established by the usual method for radiation
chimeras. Adult (8 week old) mdx mice were lethally gamma-ray
irradiated (10 Gy) using Gamma Cell (137Cs source, Nuclear Canada,
Ontario, Canada). 40x106 bone marrow cells from GFP-Tg mice
were injected intravenously into the recipient mice within 3 hours after
radiation. The recipient mice had received ampicillin (product of Sigma
Chemicals Co., St. Louis, MO) in their drinking water (1 g/L) from 1 week
before radiation to 2 weeks after radiation and reconstitution. 4 weeks after
reconstitution, peripheral blood was obtained and tested for chimerisms by
measuring GFP+ cells with a flowcytometer. 12 weeks after
reconstitution, the muscles and lymphoid organs of the mice were examined for
muscle regeneration and chimerism, respectively.
Neonatal chimeras were established as follows
(Fig. 1). Timemated pregnant
C57BL/6 or mdx mice (at gestational day 17/18) received 20-40 mg/kg
busulfan (Sigma Chemicals Co.) subcutaneously. Busulfan-treated neonatal mice
were injected intrahepatically with either 0.1-0.2x106 fetal
liver cells or 1.0-10x106 bone marrow cells from GFP-Tg mice
according to the method of Yoder et al.
(Yoder et al., 1997). 4 weeks
after reconstitution, blood samples were collected from the tail vein and used
for chimerism tests. Chimeric mice with more than 5% donor-derived
GFP+ cells among their blood mononuclear cells were selected and
used for further studies of muscle regeneration. 4 to 13 weeks later (age 8-17
weeks), the muscles and lymphoid organs were examined.
|
Histological analysis
Chimeric mice were sacrificed by cervical dislocation. Tibialis anterior
(TA) and vastus lateralis (VL) muscles, or diaphragms, were isolated and
frozen in liquid nitrogen-cooled isopentane. Cryosections (6 µm) were
examined for GFP+ muscle fibres under a confocal laser scanning
microscope (model MRC1024ES, Bio-Rad Laboratories, Hercules, CA).
Excitation/emission wavelengths for GFP were 488 nm/522 nm. Sections were then
stained with hematoxylin/eosin (H-E).
Immunohistochemistry
For immunohistochemical examinations, serial transverse cryosections (6
µm) or cultured tissues were stained with various antibodies.
Alexa-568-conjugated monoclonal anti-dystrophin (MANDRA-1, Sigma) was a gift
from M. Imamura (National Institute of Neuroscience, Tokyo, Japan). Polyclonal
rabbit anti-desmin (ICN Pharmaceuticals, Inc.-Cappel Products, Aurora, OH) and
anti-laminin (MEDAC GmbH, Wedel, Germany), together with rhodamine-conjugated
goat anti-rabbit IgG (ICN Pharmaceuticals), were used to stain muscles. The
signals were recorded photographically using an Axiophot microscope (Carl
Zeiss, Oberkochen, Germany) and laser scanning confocal imaging system MRC1000
(Bio-Rad Laboratories).
Test for blood chimerism
Blood samples of 4-week-old busulfan-treated neonatal chimeras were
examined for chimerism. For flowcytometric analyses of chimerism, mononuclear
cells from the blood, spleen and thymus of chimeras were stained with
monoclonal antibodies, phycoerythrin- or biotin-conjugated anti-CD4 (RM4-5)
and anti-CD8 (53-6.7) (PharMingen, San Diego, CA) for donor-derived T
lymphocytes, and analyzed together with GFP and phycoerythrin-Cy5-streptavidin
(Cederlane, Westbury, NY) (Kawakami et
al., 1999a; Kawakami et al.,
1999b
). GFP fluorescence was measured at the same
excitation/emission wavelength as FITC. Flow cytometric profiles were
determined with a FACSCalibur analyzer and CELLQuest software (Becton
Dickinson Immunocytometry Systems, Mountain View, CA).
Muscle regeneration
Selected neonatal chimeras at 4 weeks of age, with >5% donorderived
GFP+ cells, were anesthetized with sodium pentobarbital (75 mg/kg)
(Abbott Laboratories, North Chicago, IL), and in some experiments
(Table 1), muscle regeneration
was induced by injecting 75 µl cardiotoxin (CTX; 10 µM, Latoxan, Rosans,
France) into the TA muscle to necrotize the muscle according to the method of
Davis et al. (Davis et al.,
1993). Some mice were left CTX-untreated. Four to 13 weeks later,
muscle regeneration and chimerism were examined.
|
Muscle fibre explantation
In order to detect muscular satellite cells in the reconstituted chimeras,
muscle fibres from extensor digitorium longus (EDL) muscles from CTX-untreated
neonatal chimeras were prepared and cultured essentially according to the
methods of Bischoff (Bischoff,
1986) and Rosenblatt et al.
(Rosenblatt et al., 1995
).
Briefly, dissected muscle was incubated with 0.5% type I collagenase
(Worthington Biochemical, Lakewood, NJ) in Dulbecco's modified Eagle's medium
(Gibco BRL, Grand Island, NY) at 37°C for 90 minutes. The muscle was
transferred to fresh growth medium, high-glucose DMEM (Gibco BRL) containing
10% FCS (Boehringer-Mannheim GmbH, Mannheim, Germany) and penicillin (200
U/ml)/streptomycin (200 µg/ml) (Gibco BRL), and incubated in a humidified
incubator at 37°C, 5% CO2 for 16 hours. The muscle mass was
triturated with a firepolished wide-mouth Pasteur pipette. Fibres were
transferred to a Matrigel (Collaborative Biomedical, Bedford, MA)-coated
Lab-Tek chamber (Nalge Nunc International, Naperville, IL) and cultured for 4
days. The fibres and attached cells were fixed with 4% paraformaldehyde in
phosphate-buffered saline at room temperature for 10 minutes. They were then
permeabilized with 0.25% Triton X-100 (Nacalai Tesque, Kyoto, Japan) at room
temperature for 20 minutes, then non-specific binding was blocked by
incubation with 5% skim milk (in PBS) for 10 minutes. The fixed fibres and
cells were stained with anti-desmin antibody at 4°C overnight and then
with rhodamine-conjugated goat anti-rabbit IgG. Samples were examined for
GFP+ and/or rhodamine+ cells under a confocal laser
scanning microscope. Excitation/emission wavelengths for rhodamine are 554
nm/573 nm.
Preparation of muscle-derived cells
Freshly isolated muscle-derived cells from neonatal chimeras were prepared
according to the method of Rando and Blau
(Rando and Blau, 1994).
CTX-untreated VL muscles from neonatal chimeras were isolated, minced and
digested with dispase II (2.4U/ml) (Boehringer-Mannheim) and 1% collagenase P
(Boehringer-Mannheim) supplemented with CaCl2 to a final
concentration of 2.5 mM. The slurry, maintained at 37°C for 45 minutes,
was triturated every 15 minutes and passed through a 37 µm nylon mesh.
Single cell suspension was washed and injected into CTX-treated (24 hours
before) TA muscles of mdx/scid mice. 4 weeks later, muscle sections
were histologically examined.
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Results |
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|
Several GFP+ fibres were readily identified in TA (Fig. 3A,B), VL (Fig. 3C,D) muscles and diaphragm (Fig. 3E,F) sections and are clearly distinct from surrounding GFP-negative fibres. Because one of the GFP+ fibres expressed dystrophin, as shown in Fig. 3G-I, the fibre is thought to be newly generated from donor-derived precursor cells (Fig. 3J-L; this figure shows positive control sections of normal C57BL/6 muscle). Although the reason for the difference of dystrophin expression in each fibre is not yet known, GFP+ but dystrophin-negative fibre was also seen.
|
GFP+ muscle fibre regeneration in neonatal chimeras
Lymphocyte chimerisms of neonatal chimeras were then examined. In order to
enhance both tolerance and blood chimerism, mice received busulfan, an
anticancer drug for lympho-myeloid neoplasms, at embryonic day 17/18, then
received either adult bone marrow or fetal liver cells from GFP-Tg mice within
16 hours of birth (Fig. 1).
Typical flowcytometry studies of the chimeras are shown in
Fig. 2C-L. 4 weeks after
neonatal injection of donor bone marrow
(Fig. 2C) or fetal liver cells
(Fig. 2G), the proportions of
GFP+ blood leukocyte were 26% or 18%, respectively. The frequency
of chimeras ranged from 1 to 64%, and mice having more than 5% donor-derived
GFP+ cells in their blood leukocytes were selected. At the time of
muscle examination, GFP+ splenocytes
(Fig. 2D,E,J,K), thymocytes
(Fig. 2H,I) and bone marrow
cells (Fig. 2F,L) were also
examined for chimerisms. Normal patterns of splenic mature T cells or immature
thymocytes were observed. The donor-derived GFP+ cells were found
to be recruited to the recipient bone marrow. The chimerisms ranged from 5 to
78% at the time when mice were killed (see
Table 1).
CTX-induced muscle regeneration of neonatal chimeras is shown in Fig. 4. The GFP+ muscle fibres of a neonatal bone marrow chimera (Fig. 4B) or a fetal liver cell chimera (Fig. 4D,F) could be detected. The frequencies of GFP+ fibres are summarized in Table 1. It is evident that the frequencies of GFP+ fibres in radiation-chimeras do not exceed 2%. They show better reconstitution efficiency in their lymphocyte chimerisms than neonatal chimeras. It is interesting to note that the donor bone marrow or fetal liver cell number of the neonatal chimeras was only 1:4-1:40 (for bone marrow cells) or 1:200-1:400 (for fetal liver cells) of adult radiation-chimera experiments; however, the frequencies of GFP+ fibres in mice with lower lymphoid chimerisms are similar to those of radiation chimeras. GFP+ fibres were also observed in the CTX-untreated neonatal chimeras (mdx as recipients) (Table 1; Experiment 6 and 7). This result suggested that the donor-derived bone marrow (Experiment 6) or fetal liver (Experiment 7) cells participate in the normal muscular regeneration in mdx mice. Muscle reconstituting efficiencies of adult bone marrow and fetal liver cells were compared. As summarized in Fig. 5, when the efficiencies were calculated as GFP+ fibres/injected cell numbers, fetal liver gave better results than bone marrow cells. Fetal livers may contain a higher frequency of muscle progenitor cells than bone marrow.
|
|
GFP+ mononuclear cells in the intact muscles of neonatal
chimeras
During the course of the study, we observed several GFP+ fibres
in the CTX-untreated muscle of neonatal bone marrow
(Fig. 4H) (C57BL/6 as
recipient) as well as fetal liver cell chimeras (data not shown), but the
frequency was low. It is evident from the H-E stained picture that the
GFP+ fibre has a peripheral nucleus, suggesting that the fibre was
generated without damage by CTX. We speculate that these fibres were derived
from GFP+ satellite cells in the normal muscle. In accordance with
this observation, we detected GFP+ mononuclear cells residing
beneath the laminin-positive basal lamina of another CTX-untreated TA muscle
(Fig. 4I). This is the typical
position in which muscle satellite cells reside. To investigate which of the
cells are myogenic progenitor cells, possibly satellite cells, and whether
they contributed to muscle generation, we performed a muscle explantation
study. After 4 days of explantation culture, desmin+ and
GFP+ mononuclear cells were found attached to a single muscle fibre
(Fig. 4J-L, M-O).
In order to confirm whether the GFP+ mononuclear cells of neonatal chimeras are myogenic progenitors, single cell suspension from CTX-untreated VL muscles was obtained and transplanted into CTX-treated TA muscles of mdx/scid mice. As shown in Fig. 4R and T, muscles of the second recipients showed GFP+ fibres that were derived from intact muscles of neonatal chimeras. Collectively, these results suggest that the GFP+ cells are located in the muscle as possible satellite cells and may be participating in muscular generation upon muscle damage, as well as under physiological condition.
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Discussion |
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It has long been known that the neonatal injection of allogeneic cells
induces tolerance to alloantigens of the donor cells and frequently
establishes a chimeric state. Very recently, Liechty et al.
(Liechty et al., 2000)
described the transplantation of human mesenchymal stem cells in
utero into sheep at an early gestational period and the site-specific
differentiation of these cells into to a variety of tissues, such as
chondrocytes, adipocytes, myocytes, cardiomyocytes, and thymic and bone marrow
stromas, without any detectable immune response against the human cells.
Butler et al. (Butler et al.,
2000
) showed that neonatally induced tolerance to alloantigens in
rats persisted, and skeletal tissue allografts survived, even though the rate
of blood cell chimerism was around 3%. Thus transplantation to neonatal or
embryonic animals is a promising approach for stem cell therapy for hereditary
diseases in animal models. The origin of satellite cells and the time at which
they first migrate into muscle tissues are not yet clear. Cossu et al.
(Cossu et al., 1983
) reported
that satellite cells have a different sensitivity to phorbol ester than
myoblasts. Taking advantage of this characteristic, the authors showed that
satellite cells appear between day 16 and 18 of embryonic development in mice.
Muscle satellite cells account for about 30% of sublaminar muscle nuclei in
neonatal mice, and this level decreases to less than 5% in adult mice (for
reviews, see Campion, 1984
;
Mazanet and Franzini-Armstrong,
1986
; Cossu and Molinaro,
1987
; Bischoff,
1994
).
These observations strongly suggested to us the idea of introducing muscle precursor cells at the earliest possible time, for example at birth. In the present study, neonatal injection of allogeneic bone marrow or fetal liver cells combined with busulfan treatment successfully induced a chimeric state in both muscular precursor cells and hematopoietic cells. Neonatal mice make it necessary to limit the cell dose and volume of intravenous or intrahepatic injections; however, neonatal chimeras produced similar muscular reconstitution to adult radiation chimeras, although neonates have less efficient blood chimerisms. The immune response against proteins to viral vectors or to newly introduced gene products presents a new obstacle for both gene therapy and cell therapy. Once the mice achieve radiation-induced or neonatally induced immunological tolerance, they can be challenged by another injection of cell transplantation without any immune response.
In order to examine whether donor cells migrate into muscles, we searched
for GFP+ cells in the CTX-untreated muscles of neonatal chimeras.
As shown in Fig. 4H,I,
GFP+ fibre (H) as well as the GFP signal beneath the
laminin-positive layer (I) was present. We then explanted muscle fibres and
cultured them for 4 days in vitro under non-differentiating conditions. It was
reported that naïve desmin+ single human muscle satellite
cells in culture develop into two types of cells, one fuses into myotubes and
the other persists for weeks among the myotubes
(Baroffio et al., 1996). The
former expresses alpha sarcomeric actin, whereas the latter expresses desmin.
It is well documented that quiescent satellite cells in the muscle express
neither muscle-specific markers, such as desmin and myosin, nor the MyoD
family of muscle-specific regulatory molecules. However, after muscle injury
(Helliwell, 1988
;
Saito and Nonaka, 1994
;
Rantanen et al., 1995
;
Molnar et al., 1996
) or short
term culture in vitro (Allen et al.,
1991
; Kaufman et al.,
1991
; Creuzet et al.,
1998
), satellite cells became desmin+ and
MyoD+. This suggests that the desmin+ cell that attaches
to a single fibre is probably a muscle satellite cell. Such cells were
observed in the muscle fibre cultures in our present study
(Fig. 4L,O), and they are
GFP+. GFP+ donor bone marrow or fetal liver cells may be
recruited as muscle satellite cells and may participate in muscle regeneration
in mdx or CTX-treated muscle.
We then examined whether the fibre-attached cells express M-cadherin
(Donalies et al., 1991;
Irintchev et al., 1994
;
Bornemann and Schmalbruch,
1994
; Beauchamp et al.,
2000
), but they were negative in our experiments (data not shown).
Beauchamp et al. (Beauchamp et al.,
2000
) reported that some (
20%) fibre-attached satellite cells
in vitro do not express M-cadherin. We observed a few fibre-attached cells, so
it is possible that M-cadherin-negative fibre-attached satellite cells were
detected in these earlier experiments. To examine whether the GFP+
mononuclear cells become GFP+ fibres, we transplanted the single
cell suspension from muscles of neonatal chimeras into immunodeficient
mdx/scid secondary recipients. As shown in
Fig. 4R,T, GFP+
fibres were generated. Muscle is a highly vascularised tissue and therefore
contamination from circulating blood cells can not be excluded; however, the
results suggest that the GFP+ cells residing in the CTX-untreated
muscles are muscle precursor cells, probably satellite cells.
Recently, De Angelis et al. (De Angelis
et al., 1999) reported that the large majority of mouse clones
showing typical satellite cell morphology were derived from the dorsal aorta
not from somites. Since the cells express several vascular cell markers, the
postnatal satellite cells may be derived from a vascular lineage. In the fetal
liver, aorta-gonad-mesonephros (AGM)-area-derived hemangioblasts differentiate
to both endothelial cells for liver vessels and hematopoietic stem cells
(Miyajima et al., 2000
).
Endothelial precursors also arise from the AGM
(Ohneda et al., 1998
). Because
the AGM area appears to be attached in clusters to the dorsal aorta, the
precursors of muscle satellite cells, vascular endothelial cells and
hematopoietic cells may derive from the same origin at an early embryonic
stage. They may move to fetal liver and then to bone marrow in adults. Thus,
the bone marrow and fetal liver may have similar cell populations from which
various types of cells arise. As shown in
Fig. 5, fetal liver cells
exceeded bone marrow cells in their myogenic potentials, and it suggests that
fetal livers contained higher proportion of myogenic progenitors than adult
bone marrows.
The frequency of donor-derived muscle fibres is still too low for the
treatment of muscular dystrophies. There are several approaches to overcome
these problems. First, it is necessary to enrich the muscular precursor cells
from bone marrow or fetal liver cells by using various monoclonal antibodies
against cell-type-specific surface markers, such as c-Met, VEGF-receptor,
Sca-1 and so on. Further trials to search for novel markers are also
necessary. Second, it is not yet known what kind of adhesion molecules are
required for the migration of precursor cells into muscle. Neonatal or
radiation-induced tolerance, combined with injections of various monoclonal
antibodies against adhesion molecules, will answer this question. Lastly,
developing or regenerating muscle may produce certain kinds of chemokines or
cytokines that control the trafficking of precursor cells. These mediators and
their receptors are likely to be critical for their migration. HGF and
TGFß are possible chemotactic factors for adult muscle satellite cells of
the rat (Bischoff, 1997), but
it is not yet known what kind of factors are responsible for bone marrow- or
fetal liver-derived precursors. Although the establishment of tolerance may
not be immediately applicable to clinical trials, the experimental system,
together with the above-mentioned strategies for the proper reconstitution of
muscle, will provide valuable information for future clinical application.
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Acknowledgments |
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