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Original Paper
Cells Tissues Organs 2001;169:12–20
The Dynamic in vivo Distribution of
Bone Marrow-Derived Mesenchymal
Stem Cells after Infusion
Jizong Gao
a
James E. Dennis
a
Raymond F. Muzic
b
Magnus Lundberg
a
Arnold I. Caplan
a
a
Skeletal Research Center, Department of Biology and
b
Department of Radiology, Case Western Reserve University,
Cleveland, Ohio, USA
Accepted after revision: July 25, 2000
Dr. Arnold I. Caplan
Skeletal Research Center, Department of Biology
Case Western Reserve University
2080 Adelbert Road, Cleveland, OH 44106-7080 (USA)
Tel. +1 216 368 3562, Fax +1 216 368 4077
ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
© 2001 S. Karger AG, Basel
Accessible online at:
www.karger.com/journals/cto
Key Words
Mesenchymal stem cells
W Indium-111-oxine labeling W
Infusion W Imaging W Rat
Abstract
Bone marrow-derived mesenchymal stem cells (MSCs)
have the potential to differentiate along different mes-
enchymal lineages including those forming bone, carti-
lage, tendon, fat, muscle and marrow stroma that sup-
ports hematopoiesis. This differentiation potential
makes MSCs candidates for cell-based therapeutic strat-
egies for mesenchymal tissue injuries and for hemato-
poietic disorders by both local and systemic application.
In the present study, rat marrow-derived MSCs were ex
vivo culture-expanded, labeled with
111
In-oxine, and in-
fused into syngeneic rats via intra-artery (i.a.), intrave-
nous (i.v.) and intraperitoneal cavity (i.p.) infusions. In
addition, for i.a. and i.v. infusions, a vasodilator, sodium
nitroprusside, was administered prior to the cell infusion
and examined for its effect on MSC circulation. The
dynamic distribution of infused MSCs was monitored by
real-time imaging using a gamma camera immediately
after infusion and at 48 h postinfusion. After 48 h,
radioactivity in excised organs, including liver, lungs,
kidneys, spleen and long bones, was measured in a gam-
ma well counter and expressed as a percentage of
injected doses. After both i.a. and i.v. infusion, radioac-
tivity associated with MSCs was detected primarily in the
lungs and then secondarily in the liver and other organs.
When sodium nitroprusside was used, more labeled
MSCs cleared the lungs resulting in a larger proportion
detected in the liver. Most importantly, the homing of
labeled MSCs to the marrow of long bones was signifi-
cantly increased by the pretreatment with vasodilator.
These results indicate multiple homing sites for injected
MSCs and that the distribution of MSCs can be in-
fluenced by administration of vasodilator.
Copyright © 2001 S. Karger AG, Basel
Abbreviations used in this paper
CFU-F fibroblastic colony-forming cell
DMEM-LG Dulbecco’s modified Eagle’s medium-low glucose
FBS fetal bovine serum
i.a. intra-artery infusion
i.p. intraperitoneal cavity infusion
i.v. intravenous infusion
MSCs mesenchymal stem cells
VCAM-1 vascular cell adhesion molecule-1
Imaging of Infused MSCs
Cells Tissues Organs 2001;169:12–20
13
Introduction
Bone marrow stroma is a complex mesenchymal con-
nective tissue that contains a subset of cells termed mes-
enchymal stem cells (MSCs) [Caplan, 1991]. MSCs have
the potential to differentiate into different phenotypic
lineages forming bone, cartilage, muscle, tendon, liga-
ment, fat, muscle and marrow stroma [Bruder et al.,
1998a, b; Johnstone et al., 1998; Young et al., 1998; Pit-
tenger et al., 1999]. Culture-expanded MSCs have been
tested in preclinical models for the repair of bone [Bruder
et al., 1998a], cartilage [Johnstone and Yoo, 1999] and
tendon/ligament [Young et al., 1998] by local delivery of
MSCs within an appropriate matrix. Because MSCs are
able to differentiate into osteoblasts, a potential thera-
peutic application of MSCs would be to modulate or cure
age-related osteoporosis where decreased bone mass is
postulated to result from diminished osteogenesis [Parfitt
et al., 1995; Jilka et al., 1996]. In the case of osteoporosis,
local introduction of MSCs may not be efficient since
osteoporosis is a systemic disease. With this in mind, sys-
temic administration of MSCs would be required as a
therapeutic procedure.
Another function of marrow-derived MSCs is to sup-
port hematopoiesis by providing a supportive connective
tissue microenvironment, including the synthesis of cer-
tain regulators and cytokines for hematopoietic stem cell
proliferation and differentiation [Dexter et al., 1977; Gor-
don et al., 1990; Haynesworth et al., 1996; Weimar et al.,
1998]. Disruption of the marrow architecture with he-
morrhaging, loss of fat and loss of stromal components is
commonly found in patients after cytotoxic chemothera-
py [Ishida et al., 1994]. Therefore, there is a need to recon-
stitute the bone marrow stroma to augment the recovery
of hematopoietic function [Lazarus et al., 1995]. Koc et al.
[2000] intravenously (i.v.) coinfused human culture-ex-
panded autologous MSCs and hematopoietic stem cells
into the advanced breast cancer patients after chemother-
apy and found rapid hematopoietic recovery.
Since bone marrow-derived MSCs can be isolated
from marrow aspirates, expanded in vitro with many pas-
sages without loss of osteogenic potential [Caplan, 1991;
Haynesworth et al., 1992; Bruder et al., 1997], MSCs have
the potential of being gene therapy vehicles following
transduction with viral vectors that contain specific genes
[Allay et al., 1997]. Transduced MSCs have been deliv-
ered systemically in vivo and their secretory products
were found in different organs months later [Piersma et
al., 1983; Li et al., 1995; Allay et al., 1997; Chuah et al.,
1998; Pereira et al., 1998; Horwitz et al., 1999; Hou et al.,
1999; Oyama et al., 1999]. In a recent study [Xu et al.,
1999], MSCs transduced with a retroviral vector encoding
green fluorescent protein and neomycin resistance (neo)
genes were infused i.v. into syngeneic rats. Engrafted
MSCs were detected in the marrow of the recipient rat by
detecting the neo gene by PCR. However, no significant
differences in bone density or in the fibroblastic colony-
forming cell number were detected between the MSCs
and phosphate buffer saline infusion groups. These results
may indicate that insufficient numbers of infused MSCs
homed to the marrow or acquired a normal physiological
function.
Systemic MSC applications, including treatment of
musculoskeletal diseases, hematopoiesis support and gene
delivery, require an understanding of the distribution
dynamics of infused MSCs. The present study investi-
gated the dynamics of the infused MSCs via different por-
tals and traced MSCs homing in different organs using
isotope labeling, whole body scanning and real-time mon-
itoring. The aim of this study was to determine the fate of
the infused MSCs and to maximize systemic distribution
through the use of alternative delivery portals and the use
of vasoactive agents.
Materials and Methods
Rat bone marrow-derived MSCs were culture-expanded, labeled
with
111
In-oxine, and infused via various transferal portals to the syn-
geneic rats. In some cases, vasodilator was administered prior to the
cell infusion. The dynamic distribution of the infused MSCs was
monitored by the real-time imaging. The concentration of radioactiv-
ity in different excised organs was detected by a well counter. These
separate assays are outlined in figure 1.
Cell Culture
Cell isolation and culture procedures for MSCs in the authors’
laboratory have been established and published previously [Dennis
et al., 1992; Lennon et al., 1995]. Briefly, tibiae and femurs were
aseptically harvested from 3- to 4-month-old Fisher F-344 rats and
the adherent soft tissue was removed. The proximal end of the femur
and the distal end of the tibia were excised at a level just into the
beginning of marrow cavity. After the epiphyses were removed,
whole marrow plugs were obtained by flushing the bone marrow cav-
ity with a syringe (18-gauge needle) filled with Dulbecco’s modified
Eagle’s medium-low glucose (DMEM-LG; Sigma) supplemented
with antibiotic-antimycotic solution (penicillin G sodium: 100 U/ml,
streptomycin sulfate: 100 Ìg/ml, amphotericin B: 0.25 Ìg/ml; Gibco/
BRL) and 10% fetal bovine serum (FBS) of selected lots (Germini)
[Lennon et al., 1995]. The marrow plugs were dispersed to obtain a
single cell suspension by sequentially passing the dispersions through
18- and 22-gauge needles. The cells were centrifuged and resus-
pended with DMEM-LG containing 10% FBS. After counting in a
hemocytometer following an acetic acid disruption of red blood cells,
nucleated cells were plated at a density of 5.0!10
7
/100-mm culture
14
Cells Tissues Organs 2001;169:12–20
Gao/Dennis/Muzic/Lundberg/Caplan
Fig. 1.
Diagram showing the experimental
protocol including isolation and culture ex-
pansion of MSCs,
111
In-oxine labeling, cell
infusion and whole body imaging.
dish and incubated at 37
°
C in a humidified atmosphere of 95% air
and 5% CO
2
. The first medium change was after 4 days and twice a
week thereafter. When these primary MSCs reached 80–90% of con-
fluence, they were trypsinized, counted and passaged at a density of
0.5–0.7!10
6
/100-mm culture dish and are referred to as the 1st pas-
sage MSCs. As these first passage MSCs reached 80% of confluence,
they were labeled with
111
In-oxine by Mallincrodt, Cleveland, Ohio,
as described below. First passage MSCs were used for all of the exper-
iments in this study.
Indium Labeling of the Cells
MSCs in complete culture medium were stored on ice for transfer
to Mallincrodt approximately 5 h prior to infusion. Cells were
digested by 0.25% trypsin-EDTA (Gibco) for 10 min and centrifuged
at 320 g for 5 min. The cell pellet was resuspended in serum-free
medium and the cell number was determined. The cell suspension
was mixed with
111
In-oxine at 50–60 ÌCi/10
6
cells and incubated for
10 min. The
111
In-oxine radiolabeling efficiency of MSCs is about
70–80%, resulting in a specific activity of approximately 40 ÌCi/10
6
cells. The radiolabeled MSCs were aliquoted at 1–1.3!10
6
cells/ml.
Preliminary experiments showed that the viability and growth of
these labeled MSCs were not adversely affected by this labeling pro-
cedure (data not shown); the level of radioisotope was sufficient to
produce high quality images taken with a gamma camera. These
labeled MSCs were then transported to the Nuclear Medicine De-
partment of University Hospital at Case Western Reserve Universi-
ty, and infusion of these cells was done within 1 h followed by whole
body scanning and real-time imaging.
Infusion of
111
In-Labeled MSCs via Different Portals and
Dynamic Imaging
The infusion portals included femoral vein (i.v.), femoral artery
(i.a.) and intraperitoneal cavity (i.p.). Blood vessel cannulation of
these syngeneic Fisher F-344 rats was done by the commercial sup-
plier (Charles River, Wilmington, Mass.) prior to transport to our
site. The animals were anesthetized by intraperitoneal injection of
ketamine (800 mg/kg) and xylazine (10 mg/kg). A 1-ml cell suspen-
sion was infused via a cannulated tube that was then flushed with 0.2
to 0.3 ml of normal saline in order to infuse cells remaining in the
tubing. Radioactivity in the syringe was measured before and after
injection to determine the infused counts. Results from pilot studies
demonstrated that most radioactivity was localized in the lungs via
i.a. or i.v. injections even after 48 h of infusion. We postulated that
the reason for this distribution may be due to the size of the MSCs
(average of about 20–30 Ìm, unpubl. data) relative to the pulmonary
capillaries that are 14 Ìm in diameter on average [Richardson, 1976],
which may have impeded the infused MSCs from passing through
the lung circulation. Therefore, in some cases, the vasodilator, sodi-
um nitroprusside, was administered at the dosage of 0.001 g/kg body
weight prior to the infusion of cell suspension. In order to test the
effectiveness and duration of sodium nitroprusside administration,
arterial blood pressure measurements were performed before and
after sodium nitroprusside injections. Within 1 min postinjection,
blood pressure dropped by 50% and recovered to 90% of preinjection
values in 6–7 min (data not shown). For intraperitoneal cavity infu-
sion, 1 ml of labeled cell suspension was directly injected into the
cavity with a 23-gauge needle. Planar whole body images were
acquired with Siemens E.Cam scanner (Hoffman Estates, Ill.) using a
medium energy collimator. Scanning was performed for 15 min at
one frame per minute (fig. 2). Whole body scanning was repeated
48 h after infusion.
111
In Distribution by Organ
At 48 h postinjection, immediately following the imaging, ani-
mals were euthanized by overdose anesthesia, and organs including
liver, lungs, spleen, kidneys and long bones were harvested. These
organs were weighed and assayed for radioactivity using a 1282
Compugamma (LKB Wallac, Gaithersburg, Md.). Unlike the other
organs, the liver was too large to assay in toto. Consequently, a piece
of it was sampled and its radioactivity concentration was deter-
mined. The concentration was then scaled based on the mass of the
i.a.
Imaging of Infused MSCs
Cells Tissues Organs 2001;169:12–20
15
Fig. 2.
Planar whole body images were ac-
quired with Siemens E.Cam scanner using a
medium energy collimator. Scanning was
performed for 15 min at one frame per min-
ute and the composite image was finally
reconstructed (white-marked area at bottom
right).
Table 1.
Distribution of experimental animals into different groups
Infusion portals No vasodilator Use of vasodilator Total
5510
i.v. 6 6 12
i.p. 0 6 6
Total 11 18 28
entire liver in order to estimate the liver radioactivity. Bone tissue
was harvested from tibiae and femurs of both hind limbs. Tibias were
dislocated from the ankle joint and isolated from the proximal tibial
growth plate. The femur was harvested by dislocation from the hip
joint and from the distal femoral growth plate. All soft tissue and
periosteum were cleaned from these bones which were then pooled
together for gamma counting. Because it was difficult to quantitative-
ly harvest all bone marrow tissue from the long bone, no attempt was
made to distinguish between the radioactivity in the marrow itself
and that in the native bone.
Data Analysis. Totally, 28 rats were used for this study. These
animals were distributed into different group as summarized in
table 1. Radioactivity in each organ was expressed in two ways: by
counts per unit mass and as a percentage of injected dose. In all cases,
radioactive decay of
111
In was taken into account by decay corrected
to the time of injection. Differences of the radioactivity among the
measured organs were determined using analysis of variances
(ANOVA) at a threshold of p = 0.05 to indicate statistical signifi-
cance.
Results
Viability and Proliferation of
111
In-Oxine-Labeled
MSCs
A small aliquot of MSCs was sampled from the cell
preparation labeled by
111
In-oxine. The cell viability was
determined by exclusion of trypan blue. The average via-
bility of
111
In-oxine-labeled cells was approximately 90%
without significant differences between different cell
preparations. Labeled MSCs were plated at a density of
about 0.6!10
6
/100-mm culture dish. Cell attachment
was observed at about 3–4 h. After 2 days, cells had a typi-
cal fibroblast-like morphology and were evenly distribut-
ed on the plate (fig. 3a, b). Typically, about 80–90% of
16
Cells Tissues Organs 2001;169:12–20
Gao/Dennis/Muzic/Lundberg/Caplan
Fig. 3.
111
In-oxine-labeled MSCs prolifer-
ate in the culture plate at 2 days. These cells
had a typical fibroblast-like morphology
and were evenly distributed on the plate.
Original magnification: !4 (
a
) and !10
(
b
).
Fig. 4.
Composite image of whole body scanning immediately (
a
) and at 48 h after i.v. cell infusion (
b
), with (left) and
without (right) the use of vasodilator. Lu = Lungs; Li = liver; S = spleen; K = kidneys.
confluence was reached by day 6–7. These growth pat-
terns were similar to those of normal rat bone marrow-
derived MSCs [Lennon et al., 1995], which may indicate
that
111
In-oxine labeling did not affect the cell viability
and proliferation.
Whole Body Scanning and Dynamic Imaging
The distribution of radioactivity after infusion of the
labeled MSCs was imaged at 1-min intervals for 15 min.
Although not quantitative, this imaging provides an im-
mediate indication of where a majority of the signal
resides. A single composite image representing the sum of
all 15 images was reconstructed (fig. 2). After both i.a. and
i.v. infusion, the radioactivity was first observed to accu-
mulate in the lungs, and gradually, the radioactivity was
observed in the liver. When vasodilator was administered
prior to the cell infusion, although considerable radioac-
tivity is still observed in the lungs (fig. 4a), it was observed
Imaging of Infused MSCs
Cells Tissues Organs 2001;169:12–20
17
Fig. 5.
Composite image of whole body scanning after i.p. infusion:
radioactivity was identified in the liver, lungs, spleen and testicles.
Fig. 6.
Radioactivity concentration in different organs was scaled
based on the organ mass and the total infused dose after normaliza-
tion to the half-life of the
111
In. Most of the radioactivity accumu-
lated in the lungs and liver. When vasodilator was used, the radioac-
tivity in the lungs was decreased by about 15%; in contrast, radioac-
tivity in the liver was increased by a similar percentage (
a
), and
radioactivity in the long bone increased by about 50% (
b
).
directly from the monitor of the scanner that radioactivity
accumulated in the liver faster than in infusions without
using vasodilator. At 48 h after cell infusion, whole body
scanning was repeated. The radioactivity was observed
primarily in the liver for i.a., i.v. and i.p. infusion with
considerable amounts detected in the lungs and kidneys
after both i.a. and i.v. infusion. Vasodilator-treated rats
showed greater intensity of radioactivity in the liver than
the lungs compared to rats receiving no vasodilator. Ra-
dioactivity was also identified in the bone of the rat that
received vasodilator (fig. 4b, arrow). After i.p. infusion,
radioactivity was observed in kidneys, spleen, liver and
lungs in small amounts (fig. 5).
Organ Distribution of the Radioactivity
In order to quantify the distribution of
111
In, the spe-
cific radioactivity of each organ was calculated as a per-
centage of the total infused radioactivity related to the
particular organ mass. After both i.v. and i.a. infusion, the
radioactivity in the lungs and liver comprised about 50%
of the infused radioactivity. The use of vasodilator in-
creased the counts in the liver by about 10% and de-
creased that in the lungs by 15% (fig. 6a). Although the
percentage of radioactivity in bone was low when com-
pared to larger organs such as lungs and liver, the radioac-
tivity in the bone was increased by almost 50% with the
use of vasodilator (p = 0.008) (fig. 6b). No significant dif-
ference in gamma counts in the different organs was
observed when comparing i.a. and i.v. infusion.
Discussion
In the present study, infused MSCs lodged in the lungs
and only a small percentage of the radioactivity gradually
accumulated in the liver and spleen after infusion via
either intravenous or intra-artery. Kuppen et al. [1992]
found that
111
In-oxine-labeled lymphokine-activated kill-
5
6
18
Cells Tissues Organs 2001;169:12–20
Gao/Dennis/Muzic/Lundberg/Caplan
er cells infused via jugular vein were all detected in the
lungs up to 2 h after injection, but, after 8 h, radioactivity
was only observed in the liver and the spleen. In contrast,
even as long as 48 h after injection of MSCs in the present
study, considerable amount of radioactivity was still de-
tected in the lungs. The primary factors attributed to the
lodging of MSCs within lungs are probably cellular diame-
ter and cellular attachment potential. The average size of
rat MSCs at the 1st passage of culture is between 20 and
24 Ìm in diameter (data not shown), while the capillaries
of the lungs are about 10–15 Ìm in diameter. For compar-
ison, detached human MSCs are 2–3 times larger than
neutrophils in cytospin preparation [Koc et al., 2000].
Bone marrow-derived MSCs are attachment-competent
cells. MSCs attach in a fibronectin-facilitated manner in
in vitro culture conditions [Dennis et al., 1992] and may
specifically attach to fibronectin-rich endothelia domains
in vivo. Therefore, when the infused
111
In-oxine-labeled
MSCs circulated to the lungs, the larger MSCs may not be
able to pass through the lung capillaries or the MSCs
attach to the endothelial cells in a receptor-mediated pro-
cess. In this regard, respiratory failure after bone marrow
transplantation is one of the most common complications
in the clinical practice and may be due to abundant cells
lodging in the lung [Crawford and Petersen, 1992; Bojko
and Notterman, 1999; Leneveu et al., 1999]. When sodi-
um nitroprusside was used, as reported here, the radioac-
tivity in the lungs was decreased by 15% and that in the
liver, kidneys and bone increased by 10–50%. Sodium
nitroprusside is a strong vasodilator and also is an inhibi-
tor of aggregation and adhesion of platelets [Tinker and
Michenfelder, 1976; Krossnes et al., 1996, 1998]. There-
fore, the administration of sodium nitroprusside may
have influenced the distribution of infused MSCs by
enlarging the diameter of the pulmonary capillaries and
preventing cell adhesion and aggregation. Homing of ex
vivo expanded marrow-adherent cells has been described
after intravenous infusion in mice [Pereira et al., 1995,
1998]. About 5% of the infused cells were found in the
lungs as identified by PCR assays for a marker collagen I
gene at 5 months after infusion. Moreover, the pulmonary
vascular bed has been tested as a site for implantation of
isolated liver cells [Selden, 1984], in which rat hepato-
cytes were expanded ex vivo and infused via jugular vein.
Infused hepatocytes were identified at 24 h to 56 days
after infusion within the vascular space or capillaries of
the lungs. All these data suggest that the lung may be an
ectopic binding site for different types of cells or that cul-
tured cells lodge there due to their size or lack of deforma-
tion properties compared to the blood cells. Specific
receptor was not identified on the epithelial cells of the
lungs and the effect of these lodged cells on the function of
lungs has not yet been critically evaluated.
In the present study,
111
In-oxine was chosen as the
labeling agent, which has been widely used for labeling of
many cell types.
111
In-oxine is a lipophilic agent with
67.5 h half-life and emits gamma rays suitable for imag-
ing. These physical characteristics of
111
In have permitted
computer-assisted imaging with a scintillation camera for
the study of kinetics as well as the organ distribution of
labeled cells [Thakur, 1983; Abreo et al., 1985]. Further,
the viability of labeled cells was higher using
111
In-oxine
(90%) compared with
18
-F-FDG (80%) and
99m
Tc (85%)
[Botti et al., 1997]. In a pilot study, we observed that
the viability of
111
In-oxine-labeled MSCs at the dose of
40 ÌCi/10
6
MSCs was about 90% using the trypan blue
exclusion method. These labeled cells grew well after they
were plated and cultured under the standard conditions.
Similar results of cell proliferation and biological func-
tions were reported for
111
In-oxine-labeled lymphocytes
[Zakhireh et al., 1979; Kuyama et al., 1997]. These data
confirmed that the
111
In-oxine is a safe, non-cell-toxic and
effective labeling agent.
Bone marrow transplantation is a common procedure
for the recovery of hematopoietic function following se-
vere damage by conventional high-dosage cytotoxic che-
motherapy or by radiation exposure and for the cure of
hematopoietic disease such as leukemia. In the present
study, only a small percentage of infused MSCs lodged in
the marrow, even when vasodilator was administered.
Pretransplantation chemo- or radioablation of the bone
marrow may increase the homing of infused MSCs. Piers-
ma et al. [1983] infused chromosome-marked bone mar-
row cells to a mouse that had been given lethal total body
irradiation. At 1 day after the transplantation, 72% of
donor fibroblastic colony-forming cells (CFU-F) had
reached the recipient bone marrow, indicating a highly
specific lodging of CFU-F within marrow in these ani-
mals. Even 3 months after transplantation, donor CFU-F
was still detectable and comprised about half of the femo-
ral CFU-F population. Vascular cell adhesion molecule-1
(VCAM-1) is expressed by the marrow stromal cells [Ja-
cobsen et al., 1996] and may play an important role in the
interchange of cells between bone marrow and blood.
After gamma-irradiation to deplete the marrow, the label-
ing intensity of VCAM-1 on reticular and endothelial cells
was increased [Jacobsen et al., 1996]. Irradiation of mar-
row may also modify the marrow-blood barrier to facili-
tate the lodging of the circulating infused cells [Tavassoli,
1979; Tavassoli and Hardy, 1990]. Marrow depletion
Imaging of Infused MSCs
Cells Tissues Organs 2001;169:12–20
19
may, therefore, be another way to improve the homing of
infused MSCs.
The distribution of MSCs to different organs after
infusion by different portals may indicate that these
MSCs may circulate in the blood or lymphatic flow and
eventually home in different organs. These results are
supported by other studies where the systemic infusion or
local injection of ex vivo expanded MSCs have been
reported [Pereira et al., 1995; Oyama et al., 1999]. Since
culture-expanded MSCs can be transfected using retrovi-
ruses and express high-level marker gene in vitro and in
vivo [Allay et al., 1997; Oyama et al., 1999], the technique
of MSCs in vitro expansion and infusion may hold prom-
ise as part of gene therapy. The multiorgan homing of the
infused MSCs may facilitate their use in gene therapy to
different organs if we will be able to guide these gene-
modified MSCs to the location of particular interest. Last-
ly, if the lodging efficiency of MSCs to bone marrow could
be enhanced, systemic administration of osteoprogenitor
cells, MSCs, may provide all bony sites with osteogenic
cells capable of combating age-related osteoporosis.
Acknowledgement
The authors thank Dr. Donald Lennon for MSC preparation,
Debbie Fein-Krantz for animal care, Pat Devlin and Nicole Marcan-
tonio for assistance with the whole body scanning, and Dr. N.R.
Prabhakar and Dr. D.D. Kline for assistance with the blood pressure
measurement. This study was supported by grants from National
Institutes of Health. M.L. was supported by grants from The Swedish
Medical Society and The Fulbright Commission.
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