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PLENARY PAPER
From the Department of Veterans Affairs Medical
Center, and the Department of Medicine, Medical University of
South Carolina, Charleston, SC.
It has been reported that mononuclear cells harvested from
murine skeletal muscle are capable of hematopoietic reconstitution of
lethally irradiated mice. First, the nature of the hematopoietic progenitors in the muscle of C57BL/6-Ly-5.1 mice was examined by means
of methylcellulose culture. The types and incidences of
colonies grown from muscle mononuclear cells were different from those
cultured from bone marrow (BM) or peripheral blood mononuclear
cells. The next step was to examine the origin of the hematopoietic
progenitors and stem cells in the muscle with the use of Ly-5.2 mice
that had been made chimeric by transplantation of Ly-5.1 BM cells. The
percentages of Ly-5.1 cells cultured from the muscle of the chimeric
mice correlated with those cultured from BM, indicating BM origin of
hematopoietic progenitors in the muscle. Long-term hematopoietic
engrafting cells in the muscle of the chimeric mice were also derived
from BM. However, mobilization of progenitors into circulation by
granulocyte colony-stimulating factor did not change the population of
hematopoietic progenitors in the muscle. It is proposed that
hematopoietic progenitors and stem cells in the muscle tissue are of BM
origin but their transition from BM to muscle may be a slow process.
(Blood. 2001;98:2008-2013) It has been held for decades that, in organ
systems with regenerative ability, populations of cells called stem
cells exist and are able to self-renew and generate committed
progenies. It has also been generally believed that stem cells possess
organ/tissue specificity. However, this dogma was recently challenged
by a number of reports that a variety of cells, including those in the
hematopoietic, neuronal, and muscular organs, have the potential to
differentiate into tissues other than those specified in their origins.1-13 For example, bone marrow (BM) cells have been
shown to be capable of regenerating a number of mesenchymal tissues, such as bone, cartilage, and muscle1-7; neuronal cells
have been reported to be capable of differentiation into hematopoietic
cells8,9; and it was reported that BM cells are also
capable of hepatocyte regeneration.10-12
Equally strikingly, it has recently been reported that mononuclear
cells harvested from murine skeletal muscle are capable of
hematopoietic reconstitution of lethally irradiated
mice.7,13 These observations not only raised important
questions about cell fate specification in developmental biology but
also offered the potential of medical utility of the ectopic stem cells
for the reconstitution of hematopoiesis. In this report, we have
examined the nature and origin of the hematopoietic progenitors and
stem cells in the muscle by using clonal cell culture and
transplantation techniques.
Cytokines
Monoclonal antibodies
Mice C57BL/6-Ly-5.1 mice and C57BL/6-Ly-5.2 mice were purchased from Jackson Laboratories (Bar Harbor, ME) and Charles River Laboratories (Raleigh, NC), respectively. The Institutional Animal Care and Use Committee of the Department of Veterans Affairs Medical Center approved the animal studies. In order to study the origin of the hematopoietic cells in the muscle, we used Ly-5.2 mice that had been made chimeric by transplantation of BM cells from Ly-5.1 mice. As will be described in more detail later, we used 4 groups of chimeric mice that were survivors of studies described previously.14 Four additional groups of chimeric mice were prepared specifically for the current study by transplanting unfractionated or CD34
BM cells of Ly-5.1 mice into Ly-5.2 mice after lethal (950-cGy) irradiation.
Cell preparation Muscle mononuclear cells were prepared by means of minor modifications of the method described by Yablonka-Reuveni and Nameroff.15 This method has been used for isolation of the muscle mononuclear cells that were capable of hematopoietic reconstitution.13 Hind legs of 5- to 7-week-old Ly-5.1 mice or chimeric Ly-5.2 mice were separated just above the head of femurs following dislocation of hip joints. Muscles were then harvested on a dissecting microscope (Leica MZ6) (Heerburg, Switzerland), with care being used to avoid cutting bones. After removal of fat, epimysium, tendons, and internal connective tissues, the muscles were minced with scissors and incubated with constant agitation for 45 minutes at 37°C in 0.1% trypsin (Life Technologies, Grand Island, NY). Cells were released from the tissue fragments by vigorous trituration. Pooled cells were filtered through a 40-µm nylon mesh, washed, and resuspended in -modification of Eagle medium
(-MEM) (ICN Biochemicals, Aurora, OH). The samples were further
purified by discontinuous density-gradient centrifugation by means of
Percoll (Amersham Pharmacia Biotech, Piscataway, NJ).15
Here, the samples were centrifuged at 15 000g for 5 minutes
at 8°C in a fixed angle rotor, and mononuclear cells were collected
from the 20% to 60% interface.15 Peripheral blood (PB)
was collected by cardiac puncture with the use of methoxyflurane anesthesia, and BM cells flushed from femora and tibiae were made into
single cell suspension by repeated pipetting. Mononuclear cells were
prepared from PB and BM cells by Percoll. For determining the origin of
engrafting cells, we sorted the muscle mononuclear cells of chimeric
mice using a FACSVantage (Becton Dickinson, San Jose, CA)
fluorescence-activated cell sorter (FACS).
Clonal cell culture Methylcellulose culture was performed in 35-mm Petri dishes (Becton Dickinson Labware, Lincoln Park, NJ). Unless otherwise specified, 1 mL culture mixture contained designated numbers of mononuclear cells,-MEM, 1.2% 1500-cP methylcellulose
(Shinetsu Chemical, Tokyo, Japan), 1% deionized fraction V bovine
serum albumin (Intergen, Purchase, NY), 0.1 mM 2-mercaptoethanol
(Sigma-Aldrich, St Louis, MO), 30% fetal calf serum (Intergen), and
TPO, SF, EPO, IL-3, and IL-11. Dishes were incubated at 37°C in a
humidified atmosphere with 5% CO2, 5% O2, and
90% N2. Erythroid colony-forming units (CFU-Es) were
counted on day 2 of culture, and all other colonies consisting of 50 or
more cells were scored on an inverted microscope after 8 days of
culture. Specific cellular composition of the colonies was determined
by means of cytospin preparations of individual colonies stained with
May-Grünwald-Giemsa on days 8 to 14 of culture. Abbreviations of
colony types are as follows: erythroid burst-forming units (BFU-Es);
granulocyte and/or macrophage (GM) colonies; mixed colonies containing
erythroid and myeloid cells and megakaryocytes
(GEMM).16
Transplantation The hematopoietic engrafting capability of muscle and BM cells of the chimeric mice were studied by injecting test cells into the tail vein of recipient mice after a single 950-cGy dose of total body irradiation of recipients using 4 × 106 V linear accelerator. To prevent posttransplantation death, designated types of radioprotective cells were also transplanted. Two or 6 months later, PB was obtained from the retro-orbital plexus of the recipients with the use of heparin-coated micropipettes (Drummond Scientific, Broomall, PA). Red blood cells were lysed by 0.15 M NH4Cl, and the samples were analyzed for Ly-5 expression on a FACSCalibur (Becton Dickinson). Cells in the T-cell, B-cell, granulocyte, and monocyte/macrophage lineages were analyzed by staining with PE-conjugated anti-Thy-1.2, anti-CD45R/B220, anti-Gr-1, and anti-Mac-1.Progenitor mobilization by G-CSF Ly-5.1 mice were injected at 12-hour intervals subcutaneously with 125 µg/kg human recombinant G-CSF in 0.1 mL phosphate-buffered saline (Life Technologies) for 5 consecutive days. Three hours after the last injection, PB and muscles were harvested. Mononuclear cells of PB and muscles were plated in methylcellulose in the presence of TPO, SF, EPO, IL-3, and GM-CSF. On day 8 of culture, colonies were scored. Mice that received no G-CSF treatment were used as controls.Statistical analysis Student t test was used to determine statistical significance. Correlation was determined by using Pearson correlation coefficient.
Hematopoietic progenitors in the muscle We examined the nature and the incidence of the progenitors in the muscle of Ly-5.1 mice by using methylcellulose culture and compared them with the progenitors in BM and PB. The results are presented in Table 1. For measurement of CFU-Es, we plated 5 × 104 muscle, BM, or PB mononuclear cells per dish. The incidence of day-2 CFU-Es of muscle was less than one fiftieth that of BM. PB had no CFU-Es even when 2 × 105 cells were plated (data not shown). For analysis of day-8 colony-forming units in culture (CFU-Cs), we plated the numbers of cells that would yield 30 to 40 colonies per dish. The incidence of day-8 CFU-Cs in muscle was approximately one tenth that of BM and 10 times higher than PB. The incidences of BFU-Es and mast cell progenitors in the muscle, relative to total day-8 CFU-Cs, were much lower than those in PB.
We then performed a time course study of colony formation from
muscle, PB, and BM. On day 8, 10, 12, and 14 of culture, all colonies
from quadruplicate cultures were individually lifted from
methylcellulose culture, centrifuged to glass slides by means of a
Cytospin 2 (Shandon Southern, Sewickley, PA), and stained with
May-Grünwald-Giemsa for determination of cellular composition. Various types of single-lineage and multilineage colonies were seen.
Predominant types of colonies are presented in Table
2. Similarly to the multilineage colonies
cultured from BM cells,16 a variety of lineage
combinations were seen in the muscle-derived multilineage colonies,
such as colonies containing neutrophils, macrophages, mast cells,
erythrocytes, and megakaryocytes. Again, the relative incidence of
muscle-derived erythroid bursts was very low. The number of colonies
consisting of undifferentiated blast cells in cultures of muscle
cells gradually increased during incubation. In replating studies,
these blast cell colonies proved to be committed to B-cell lineage
(data not shown). Together, these results indicated that the
hematopoietic progenitors in the muscle constitute a distinct
population of progenitors.
Origin of the hematopoietic progenitors and stem cells in the muscle Next, we examined the origin of the progenitors and stem cells in muscle by using chimeric mice. The details of the conditions for creating the chimera for progenitor studies are presented in Table 3. In experiments 1 through 5, muscle and BM cells of the chimeric mice were cultured in methylcellulose media for 8 days, and the cells in the colonies were individually picked, pooled, and analyzed for Ly-5 expression. Results of colony formation and analysis of the percentage of donor (Ly-5.1) cells in the colonies are also presented in Table 3. There was significant correlation between the percentage of Ly-5.1 cells in the pooled colonies from the muscle and from the BM (Pearson correlation coefficient, 0.961; P < .01). For example, in experiment 5, in which all mice revealed very high levels of donor (Ly-5.1) cells in PB, the cells cultured from both BM and muscles were derived completely from Ly-5.1 BM cells. The fact that we were able to analyze groups of mice with levels of chimerism between 25% and 99% ensured an accurate sampling of the population. These observations indicated that hematopoietic progenitors in the muscle are derived from BM.
We then tested the engrafting capabilities of the muscle cells of the
chimeric mice by transplantation into secondary Ly-5.2 mice. In our
preliminary studies, transplantation of 1 × 105 muscle
mononuclear cells of healthy adult Ly-5.1 mice yielded low-level (about
1% or less) hematopoietic chimerism in primary recipients 6 months
after transplantation (data not shown). Therefore, we transplanted more
than 1 × 105 muscle cells of the chimeric mice in the
secondary-transplantation studies. The cells harvested from the muscle
or BM of chimeric mice (experiments 5 and 6 in Table 3) were injected
into lethally irradiated Ly-5.2 mice along with radioprotective cells
(Table 4). Six months later, PB was
collected from the Ly-5.2 secondary-recipient mice, and the levels of
engraftment were analyzed by flow cytometry. Although the levels of
chimerism were low in the recipients of muscle cell transplantation,
multilineage reconstitution by Ly-5.1 cells was clearly observed in
both groups of recipients (Table 4, Figure
1). These results indicated that some
hematopoietic stem cells in the muscle are derived from BM.
Recent reports from Gussoni et al7 and Jackson et
al13 suggested the existence, in the muscle, of a
Ly-5
Effects of mobilization of hematopoietic progenitors Our studies using chimeric mice suggested communication between the hematopoietic cell population in the muscle and BM. In the next experiment, we tested the effects of G-CSF-induced progenitor mobilization on the progenitors in the muscle. Administration of G-CSF caused more than 20-fold increases in the numbers of CFU-Cs, CFU-GMs, and CFU-GEMMs in PB (Table 6). However, the number and type of progenitors in muscle tissue were not affected by administration of G-CSF.
It was reported recently that murine skeletal muscles contain cells that are capable of significant hematopoietic reconstitution. Gussoni et al7 noted the presence in the muscle tissue of side population (SP) cells that had been reported to be highly enriched for hematopoietic stem cells.18 The muscle SP cells were capable not only of muscular regeneration but also of significant hematopoietic engraftment when transplanted into lethally irradiated syngeneic mice.7 Subsequently, Jackson et al13 reported that cultured mononuclear cells from muscle of adult mice are capable of hematopoietic reconstitution. They also attributed the hematopoietic engraftment to the muscle SP cells and speculated that skeletal muscle stem cells, ie, satellite cells, are responsible for the hematopoietic activity. In this study, we attempted to characterize the hematopoietic
progenitors and stem cells that are present in muscle tissue. Care was
taken to harvest cells only from the muscle tissue and not to
contaminate the samples with BM cells. We demonstrated that both the
types and the relative incidences of the hematopoietic progenitors in
muscle are different from those in PB or BM. However, methylcellulose
culture studies of the muscle cells of chimeric mice revealed
significant correlation between the incidences of donor origin
progenitors in the muscle and the BM. We had a significant number of
stable chimeric mice from other experiments that provided the
opportunity to analyze various donor populations of stem cells. Whether
we used CD34+, CD34 Following the initial identification of long-term hematopoietic
engrafting cells in murine muscle,7,13 investigators in other laboratories19-21 also documented hematopoietic
populations in the muscle. However, there are some discrepancies
concerning the level of hematopoietic reconstitution. While Gussoni et
al7 and Jackson et al13 revealed high levels
of hematopoietic engraftment by the muscle cells, Farace et
al19 and Bauermeister et al20 described lower
engrafting potentials of the muscle cells. There are a number of
technical differences in the preparation of the test cells. Although
our studies indicated lower levels (1% to 9%) of engraftment, our
analysis was based primarily on secondary transplantation of chimeric
animals. Gussoni et al7 used muscle SP cells from young
(3- to 5-week-old) mice. Jackson et al13 used muscle cells
that were cultured for 5 days under conditions for satellite cell
growth. Both groups suggested that the Ly-5
The authors wish to thank Drs Fumihiko Ishikawa, Akaru Ishida, and Takao Deguchi for assistance in breeding of experimental mice; Dr Pamela N. Pharr, Anne G. Livingston, and Karen A. Rivers for assistance in preparation of this manuscript; Dr Haiqun Zeng for assistance in FACS sorting; and the staff of the Radiation Oncology Department of the Medical University of South Carolina for assistance in the irradiation of the mice.
Submitted March 12, 2001; accepted May 25, 2001.
Supported by grants PO1-CA78582 and RO1-DK54197 from the National Institutes of Health; the Office of Research and Development, Medical Research Services, Department of Veterans Affairs; The Japan Society for the Promotion of Science grant JSPS-RFTF97-I-00201; and Tokai University General Research Organization.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Makio Ogawa, Department of Veterans Affairs Medical Center, 109 Bee St, Charleston, SC 29401-5799; e-mail: ogawam{at}musc.edu.
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Abstract
Introduction
