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j o u r n a l o f s u r g i c a l r e s e a r c h -- ( 2 0 1 3 ) e 1ee 8
Available online at w
journal homepage: www.JournalofSurgicalResearch.com
CXCL12/CXCR4 axis promotes mesenchymal stem cellmobilization to burn wounds and contributes to wound repair
Changjiang Hu, PhD,a,b,1 Xin Yong, PhD,a,b,1 Changzhu Li, PhD,a,* Muhan Lu, PhD,b
Dengqun Liu, PhD,c Lin Chen, PhD,b Jiongyu Hu, PhD,a Miao Teng, PhD,a
Dongxia Zhang, PhD,a Yahan Fan, PhD,b and Guangping Liang, PhDa,**a Institute of Burn Research, Southwest Hospital, Third Military Medical University, Chongqing, P.R. Chinab Institute of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. Chinac Institute of Combined Injury, State Key Laboratory of Trauma, Burn and Combined Injury, College of Preventive Medicine, Third Military
Medical University, Chongqing, P.R. China
a r t i c l e i n f o
Article history:
Received 19 September 2012
Received in revised form
16 December 2012
Accepted 10 January 2013
Available online xxx
Keywords:
Bone marrowederived
mesenchymal stem cells
Burn wound
CXCL12
CXCR4
* Corresponding author. Institute of Burn ReTel.: þ86 023 68754149; fax: þ86 023 6546039** Corresponding author. Institute of Burn ReTel.: þ86 023 68754149; fax: þ86 023 6546039
E-mail addresses: [email protected] (1 Changjiang Hu and Xin Yong contributed
0022-4804/$ e see front matter ª 2013 Elsevhttp://dx.doi.org/10.1016/j.jss.2013.01.019
a b s t r a c t
Background: Bone marrowederived mesenchymal stem cells (BM-MSCs) play a crucial role
in tissue repair. Their role in thermal burn wound regeneration and the relevant mecha-
nism, however, is rarely studied.
Methods: BM-MSCs from green fluorescent protein transgenic male mice were transfused to
irradiated recipient female C57BL/6 mice. Twenty-one days later, the female mice were
inflicted with burn wounds. The size of the burned area was measured by an in vivo fluo-
rescence imaging system, and BM-MSC chemotaxis and epithelialization were estimated by
fluorescence in situ hybridization and immunofluorescence technology. The expression of
CXCL12 and CXCR4 in the wound margin was detected by enzyme-linked immunosorbent
assay and immunohistochemistry. The importance of CXCL12/CXCR4 signaling in BM-MSC
chemotaxis was further estimated by blocking CXCR4 in vivo and in vitro.
Results: In vivo imaging results showed that BM-MSCs migrated to the injured margins.
Fluorescence in situ hybridization and immunofluorescence technology revealed that Y
chromosomeepositive cells derived from green fluorescent protein transgenic mice were
detected to be colocalized with keratin protein. Enzyme-linked immunosorbent assay
revealed increased levels of CXCL12 and CXCR4 protein in the wound sites of BM-MSC-
treated chimeric mice after burn. Immunohistochemistry also disclosed that CXCL12
levels were elevated at postburn day 7 compared with day 0. Furthermore, pretreatment of
the BM-MSCs with the CXCR4 antagonist AMD3100 significantly inhibited the mobilization
of BM-MSCs in vitro and in vivo, which attenuated wound closure.
Conclusion: BM-MSC migration to the burned margins promotes the epithelialization of the
wound, and mobilization of BM-MSCs is mediated by CXCL12/CXCR4 signaling.
ª 2013 Elsevier Inc. All rights reserved.
search, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.8.search, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.8.C. Li), [email protected] (G. Liang).equally to this study.
ier Inc. All rights reserved.
j o u rn a l o f s u r g i c a l r e s e a r c h -- ( 2 0 1 3 ) e 1ee 8e2
1. Introduction 2. Materials and methods
Bone marrowederived mesenchymal stem cells (BM-MSCs)
are a subset of nonhematopoietic cells in bone marrow char-
acterized by their capacity for self-renewal and differentiation
intomultiple cell types, including osteoblasts, adipocytes, and
chondrocytes [1]. It has been widely accepted that tissue
repair of injuries is primarily advanced by bone marrow stem
cells that migrate to the site of damage and undergo differ-
entiation, promoting structural and functional repair [2].
Studies have demonstrated that intravenous delivery of BM-
MSCs leads to their migration to the injured site of bone or
cartilage fracture [3], myocardial infarction [4], and ischemic
cerebral injury [5].
BM-MSCs can mobilize and migrate to target sites to
participate in tissue repair and regeneration. Many studies
have focused on the mechanisms of how BM-MSCs migrate to
injured tissues, and some key molecules involved in several
signaling pathways have been reported to participate in this
process, such as the CXCL12/CXCR4 pathway, whichmediates
BM-MSC migration and enhances wound healing, damage
repair, and regeneration. CXCL12 (also known as SDF-1) is
a member of a large family that promotes chemotaxis. It was
first identified as a lymphocyte- and monocyte-specific che-
moattractant under both normal and inflammatory condi-
tions [6]. Wynn et al. demonstrated that CXCR4, the receptor
for CXCL12, was highly expressed in BM-MSCs and that the
CXCL12/CXCR4 axis was involved in the migration of BM-
MSCs [7]. The CXCR4 antagonist significantly inhibited the
chemotaxis of BM-MSCs to CXCL12 [8]. In addition, the
CXCL12/CXCR4 pathwaywas shown tomediate the homing of
transplanted BM-MSCs to injured sites in the brain, and it was
shown that BM-MSCs migrated toward a CXCL12 gradient in
a dose-dependent manner [5]. These studies suggest that the
CXCL12/CXCR4 axis is required for BM-MSC migration.
Burn injuries, which are characterized by heat-induced
tissue coagulation at the time of injury, constitute a world-
wide public health problem [9]. Compared with incisional
wounds, burn wounds heal more slowly because of edema,
extensive necrosis, and relative hypoxia of the burn wound
[10]. Furthermore, it has been well established that large burn
injuries induce systemic immune dysfunction, which
endangers the patient’s life [11,12]. Advances in the field of
burn wound healing remain limited but are necessary. BM-
MSCs have shown the capacity to accelerate the healing
process of incisional wounds [13]. However, to date, there
have been few studies regarding the role of BM-MSCs in the
repair process of burns, and the related mechanism is even
less understood. In the present study, we investigated the
detailed localization and effects of BM-MSCs in burn wound
healing using a deep burn model of chimeric C57BL/6 mice
and examined the role of CXCL12/CXCR4 signaling in BM-
MSC migration. Our results showed that the transplanted
BM-MSCs primarily distributed in the hair follicles and
epidermis of the wound margin, accelerating the epithelial-
ization of the wound. The CXCL12/CXCR4 axis promoted BM-
MSC mobilization to burn wounds, which suggests that the
CXCL12/CXCR4 axis would be a novel therapeutic target for
the treatment of burn wounds.
2.1. Irradiation and transplantation
All animal experiments were approved by the Animal Care
and Use Committee of the Third Military Medical University
and were performed in compliance with the “Guide for the
Care and Use of Laboratory Animals” published by the
National Institutes of Health. Eight-week-old female C57BL/6
mice were obtained from the Third Military Medical Univer-
sity. They were housed in autoclaved cages and treated with
antibiotics (280 mg erythromycin and 320 mg gentamicin
sulfate per liter of deionized drinking water) for 10 d before
irradiation and 2 wk after irradiation. Recipient mice were
exposed to 10 Gy whole-body irradiation using a Cobalt-60
source (Theratron-780 model; MDS Nordion, Ottawa, ON,
Canada), which is a method that has been widely used to
destroy marrow [14,15]. Four hours after irradiation, 1 � 106
BM-MSCs from male green fluorescent protein (GFP) trans-
genic C57BL/6 mice (Cyagen Biosciences, Guangzhou, China)
were injected into the tail vein of female recipient mice.
2.2. Quantitative real-time polymerase chain reaction(RT-PCR) for confirmation of the chimeric model
Mouse chimerismwas evaluatedbydetecting themale-specific
gene Sry in the peripheral blood harvested from recipient mice
20 d after BM-MSC transplantation. The expression of Sry from
theperipheral bloodofmalemicewasusedasapositive control
and that from wild-type female mice as a negative control.
Genomic DNA was extracted from mouse blood with the
DNeasy Blood and Tissue Kit (Tiangen, Beijing, China) accord-
ing to the manufacturer’s instructions. Quantitative real-time
PCR was performed as described previously [16]. The primer
sequences were as follows: Sry (forward), 50-GGAGGCACAGAGATTGAAGA-30; Sry (reverse), 50-ACTCCAGTCTTGCCTGTATG;GAPDH (forward), 50-ACCCATCAC CATCTTCCAGGAG-30; and
GAPDH (reverse), 50-GAAGGGGCGGAGATGATGA C-30.
2.3. Animal burn model
A burn injury model was established 21 d after BM-MSC
transplantation, as described previously [17]. Briefly, the mice
were anesthetized by intraperitoneal injection of pentobarbital
sodium(75mg/kg). Then, a total of 1.75 cm2bodysurfaceareaof
the mouse dorsum was exposed to a 100�C water bath for 8 s.
On days 1, 3, 7, 14, 21, and 28, the entire wound area, including
the adjacent 2-mm skin margins, was collected for further
analysis of fluorescence in situ hybridization (FISH), immuno-
fluorescence (IF), enzyme-linked immunosorbent assay
(ELISA), and immunohistochemistry (IHC).
2.4. In vivo fluorescence imaging
In vivo fluorescence imaging was performed on days 1, 3, 7, 14,
21, and 28 post wounding using a Maestro In Vivo Imaging
System (Cambridge Research & Instrumentation, Boston, MA).
The excitation filter for GFP was 445e490 nm. The tunable
j o u r n a l o f s u r g i c a l r e s e a r c h -- ( 2 0 1 3 ) e 1ee 8 e3
filter was automatically stepped in 10-nm increments from
500e750 nm with an exposure time of 300 ms for the images
captured at each wavelength. The animals were placed on the
microscope stage, and then the images were taken in both
true color and pseudo color. The measurements of the burn
area were analyzed using the Maestro 2.10.0 software, which
is part of the Maestro In Vivo Imaging System. Measurements
of the wound area were taken three times by two independent
experimenters.
2.5. FISH and IF analysis
The FISH and IF analyses were performed according to the
methods described by Sato et al. [18]. In brief, cryostat sections
were incubated with primary anti-pancytokeratin antibody
(DakoCytomation, Carpinteria, CA; 1:50). After dehydration,
the tissue sections were incubated with Cy3-labeled Y chro-
mosome probes (Star*FISH; Cambio, Dry Drayton, UK) over-
night. The sections were then washed and incubated with the
anti-pancytokeratin antibody again at a 1:50 dilution. After
washing, the slides were mounted in 40, 6-diamidino-2-
phenylindole (DAPI; Invitrogen, Carlsbad, CA). The sections
were viewed with a confocal laser scanning fluorescence
microscope (Leica Biosystems, Wetzlar, Germany).
2.6. ELISA
The expression of CXCR4 and CXCL12 in the woundmargin of
mice at different times after burns was assessed by ELISA
analysis. The tissues collected from the wound of chimeric
C57BL/6mice on postburn days 1, 3, 7, 14, 21, and 28were lysed
as previously described [19]. The levels of CXCR4 and CXCL12
weremeasured using a mouse CXCR4 and CXCL12 Quantikine
Kit (R&D Systems, Minneapolis, MN) according to the manu-
facturer’s protocol.
2.7. IHC
The tissues collected from chimeric C57BL/6 mice after burns
were harvested in PBS-buffered formaldehyde, embedded in
paraffin, and sliced into 4-mm thick sections. Monoclonal anti-
bodies against CXCL12 (Abcam, Cambridge, UK) were used for
the analysis. Immunoreactivity was detected using a horse-
radish peroxidasee30-, 30-diaminobenzidine kit (Beyotime,
Shanghai, China), followed by counterstaining with hematox-
ylin, dehydration, and mounting. The representative areas
containing CXCL12-positive tissue were captured by a micro-
scope (Olympus, Tokyo, Japan) with 200� magnification.
2.8. In vitro and in vivo chemotaxis analysis blockingCXCR4
For in vitro chemotaxis analysis, 100 mL BM-MSCs (5� 105 cells/
mL) were incubated with CXCR4 antagonist AMD3100
(Cayman Chemical, Ann Arbor, MI; 5 mg/mL) or PBS as
a vehicle in the upper chamber (Corning, Corning, NY). a-MEM
medium containing both 10% (vol/vol) FBS and CXCL12 (R&D
Systems; 50 ng/mL) was in the lower well. After a 24-h incu-
bation, the migration cells were stained with 0.5% (wt/vol)
crystal violet (Beyotime) and counted in five random fields
using a light microscope at 40� magnification (Olympus). For
in vivo chemotaxis analysis, 1 � 106 BM-MSCs were pre-
incubated with AMD3100 (5 mg/mL) or PBS for 30 min and
injected into the tail veins of bone marrowedestroyed female
C57BL/6 mice. The burned model was created by the same
method described above. FISH and IF were conducted at
postburn day 14, and the wound areas were also tested using
the same method described above.
2.9. Statistical analysis
SPSS version 17.0 software (SPSS for Windows, Inc, Chicago,
IL) was used for all statistical analysis. The area measure-
ments and counts of the migrated cells were all accomplished
by two experimenters at three independent times. For the
repeatability between the two raters, the Supplementary
Table shows the intraclass correlation coefficient (ICC) of the
raters. There is no statistical difference between the raters. All
results are expressed as themean� SEM. Student paired t-test
was used to compare the differences between 2 groups, while
one-way analysis of variance was used to analyze of the data
among three or more groups. P < 0.05 was considered as
significant difference.
3. Results
3.1. Successful establishment of the chimeric mousemodel using MSCs from GFP transgenic mice
To establish the chimeric mouse model, we first identify the
GFP-labeled MSCs from GFP transgenic mice. The morphology
of the MSCs from male GFP transgenic mice was spindle-
shaped under a light microscope (Fig. 1A), and its green fluo-
rescence was observed using fluorescence imaging (Fig. 1A).
Moreover, the MSCs were positive for SCA-1, CD29, CD34, and
CD44 but negative for CD117 using flow cytometry analyses
(FACSAria cell sorter; BD, San Jose, CA; Fig. 1B). The capacity of
these MSCs to differentiate into adipocytes, osteoblasts, and
chondrocytes was confirmed in a previous study [20]. After
irradiation, the recipient female mice were transfused with
these MSCs. Sry gene, which rarely exists in wild-type female
mice, was detected in the peripheral blood of all recipients 20
d after BM-MSC transplantation (Fig. 1C). These results
showed that the bonemarrow function of the chimeric mouse
was successfully re-established.
3.2. BM-MSCs were primarily recruited around thewound margin and promoted wound healing
To investigate the distribution of the GFP-MSCs from the re-
established bone marrow, an in vivo fluorescence imaging
systemwas used to observe the localization of these cells post
burn. Figure 2A shows the images of the GFP-MSCs in the
mouse and the corresponding wound in pseudo color. It was
clearly shown that the GFP-labeled BM-MSCs migrated to the
wound site at postburn day 1, and the BM-MSCs were mainly
localized around the wound margin. The wound area gradu-
ally decreased from postburn day 1 to day 28 (Fig. 2B). These
Fig. 1 e Identification of BM-MSCs and the chimeric mouse model. (A) The morphology of BM-MSCs from male GFP
transgenic mice was observed under light microscopy (a) and fluorescence imaging (b). (B) The BM-MSCs were positive for
SCA-1, CD29, CD34, and CD44, but negative for CD117, by flow cytometry analysis. (C) Recipient mice were exposed to 10 Gy
whole-body irradiation using a Cobalt-60 source. Four hours after irradiation, 1 3 106 BM-MSCs from male GFP transgenic
C57BL/6 mice were injected into the tail veins of recipient mice. Sry gene expression in peripheral blood cells of mice was
determined using real-time quantitative RT-PCR 20 d after the BM-MSC transplantation. The expression levels were
normalized to GAPDH. The results represent the mean ± SEM of three independent experiments. *P < 0.01 versus negative
control (wild-type female mice).
j o u rn a l o f s u r g i c a l r e s e a r c h -- ( 2 0 1 3 ) e 1ee 8e4
results suggest that BM-MSCs may be involved in wound
regeneration.
3.3. BM-MSCs were located in the epidermis and hairfollicles of wound
It has been clearly shown by the above study that BM-MSCs
were primarily recruited around the wound margin, so we
Fig. 2 e BM-MSCs were primarily recruited around the woundma
was established 21 d after BM-MSC transplantation. Then in vivo
room on days 1, 3, 7, 14, 21, and 28 post-wounding using an in
pseudo color were taken. (B) The wound area was measured at
mean ± SEM (*P < 0.05, **P < 0.01, #P < 0.001 versus day 1).
hypothesize that the MSCs may promote the epithelialization
of wounded skin. Because the Y chromosomeepositive cells
were from the male mice and could represent the BM-MSC
and because pancytokeratin is a special marker of the
epithelium, we used FISH to detect the Y chromosomee
positive cells and IF to detect the pan-cytokeratin-positive
cells. As revealed in Figure 3, Y chromosomeepositive cells
were found to colocalize with pan-cytokeratin in the
rgin and promoted wound healing. (A) A burn injurymodel
fluorescence imaging was performed in a completely dark
vivo imaging system. The images in both true color and
different days post-wound. The results represent the
Fig. 3 e BM-MSCs were located in the epidermis and hair follicles of the wound. The tissue sections at wound sites were
collected on days 1, 3, 7, 14, 21, and 28 after wounding and Y chromosome-positive cells were detectedwith Y-FISH and pan-
cytokeratin (Pan-CK) were detected with IF. The nuclei were stained blue (DAPI). Then the images were merged. Bar, 50 mm.
j o u r n a l o f s u r g i c a l r e s e a r c h -- ( 2 0 1 3 ) e 1ee 8 e5
epidermis and hair follicles of the wound margin on postburn
day 1. Both the amount of the Y-chromosomeepositive cells
and the pan-cytokeratin-positive cells were increased in the
wound in a time-dependent manner. Together, these results
indicated that the BM-MSCs were recruited to the epidermis
and hair follicles, which ultimately promoted the expression
of pancytokeratin and the formation of epithelialization.
3.4. CXCL12-CXCR4 signaling was important for thechemotaxis of BM-MSCs
Because the CXCL12-CXCR4 axis is one of the most important
signals in the progression for the mobilization of cancer cells
and inflammatory cells, we hypothesize that this axis also
participates in the movement of the transplanted BM-MSCs.
We examined the expression levels of CXCL12 and CXCR4 in
the tissues from the wound margins by ELISA and IHC. As
shown in Figure 4A, the expression of CXCR4 and CXCL12
protein in the wound margins was significantly elevated at
day 7 post burn. In addition, using IHC analysis, CXCL12 was
found to be primarily expressed in the basal layer of the
epidermis and hair follicles with IHC. IHC showed that the
levels of CXCL12 were significantly elevated in BM-MSC-
treated mice at day 7 (Fig. 4D) compared with those at day
0 post burn (Fig. 4C), which is consistent with the ELISA result.
3.5. Inhibition of CXCR4 decreased BM-MSCmobilization and attenuated wound healing
To further confirm the importance of CXCL12-CXCR4 signaling
in themovement of MSCs, we observed the chemotaxis of BM-
MSCs in vitro and in vivo using the CXCR4 inhibitor. First,
Fig. 4 e CXCL12-CXCR4 signaling was important for the chemotaxis of BM-MSCs. (A,B) ELISA was used to detect the CXCR4
(A) and CXCL12 (B) protein levels in the tissue of wounded mice at different times post wounding. The data are the
mean ± SEM from three independent experiments (*P< 0.05 comparedwith day 0). (C,D) IHCwas used to analyze the CXCL12
protein expression level and localization in wound sites at postburn day 0 (C) and day 7 (D). The bar indicates 200 mm.
j o u rn a l o f s u r g i c a l r e s e a r c h -- ( 2 0 1 3 ) e 1ee 8e6
AMD3100 effectively inhibited the directional migration of
BM-MSCs in vitro compared with the control group (P < 0.05;
Fig. 5A and B). Second, the Y chromosome and pancytokeratin
double-positive epidermal cells and hair follicle cells at the
wound margins were notably decreased in the AMD3100
group, indicating that AMD3100 inhibited the mobilization of
BM-MSCs and, their ability to participate in wound repair
(Fig. 5C). Moreover, as shown in Figure 5D and E, treatment
with AMD3100 significantly attenuated wound closure
compared with the control group (PBS).
4. Discussion
Burn injury remains a challenge in the field of cutaneous
woundhealing [9]. Superficial burnsusually healwithminimal
scarring, but treatments for second- and third-degree burn
injuries remain far from optimal [21,22]. In the present study,
we demonstrated that BM-MSCs promoted the healing of
thermal burned skin using a novel model (chimeric C57BL/6
mice). After we successfully constructed the chimeric mouse
model, we found that BM-MSCsmigrated to the burn sites and
were mainly recruited to the epidermis and hair follicles.
A previous study reported that BM-MSCs accelerated the
recovery of homeostasis and promoted healing of thermal
burn wounds in a patient with an extensive skin burn [23];
however, the distribution and detailed localization of the
MSCs is not clear. This study was the first to use an in vivo
imaging system to observe the distribution of the GFP-labeled
stem cells, which clearly provided a real-time and dynamic
image of the movement of the labeled cells in vivo after burns.
We thus provided evidence that the transplanted BM-MSCs
mainly directionally migrated to the wound margin and
that their distribution was primarily around the wound.
Furthermore, we showed that Y chromosomeepositive cells
were colocalized with pan-cytokeratin-positive cells in the
hair follicles and epidermis of the wound margin. These
results indicate that MSCs accelerate skin epithelialization
after burn andmay provide clues for the clinical application of
BM-MSCs in burn wound treatment.
The possible mechanisms by which MSCs promote cuta-
neous wound repair and regeneration contain the following
aspects: paracrine action, immunomodulation, immunosup-
pression, self-differentiation, and cell fusion [24]dbut which
aspects play primary roles remains controversial. During our
study, we found that the BM-MSCs promoted the epithelial-
ization of wounded skin. However, it has yet to be determined
whether the Y chromosomeepositive cells are due to the self-
differentiation of the BM-MSCs or cell fusion. Besides, the
expression level of the soluble factors, including keratinocyte
growth factor, angiopoietin 1, and interleukin 10, may have
increased in the plasma after the BM-MSC transplantation,
especially around the wound. It is interesting and significant
to demonstrate which of the soluble factors is the most
abundant and important in further study.
Studies have shown that binding CXCL12 to its cognate
receptor, CXCR4, plays an important role in the migration of
human umbilical cord blood MSCs in vitro [25]. CXCL12 is
expressed/secreted by several tissues/organs in the body. The
most important sources of SDF-1 are bone marrow-, lymph
node-, muscle- and lung-derived fibroblasts. SDF-1 is also
secreted by liver and kidney cells and in several regions of the
centralnervoussystem[26].CXCL12expressionhasbeenshown
toincreaseunderstressconditionsandmaythusservetoattract
stem cells to sites of tissue injury [27]. It has been reported that
various organs respond to tissue damage, such as from irradi-
ation, hypoxia, or toxic agents, by increasing the expression/
secretionofCXCL12 [28,29]. Fewstudieshave focusedontherole
Fig. 5 e Inhibition of CXCR4 decreased BM-MSC mobilization and attenuated wound healing. (A) The transwell assays
showed the migration capacity of MSCs co-cultured with PBS (a) or AMD3100 (b). Bar, 100 mm. (B) The number of migrated
MSCs in two different conditions (n [ 3, *P < 0.05). (CeF) 1 3 106 BM-MSCs were pre-incubated with AMD3100 (5 mg/mL) or
PBS for 30 min and injected into the tail veins of bone marrowedestroyed female C57BL/6 mice. Next, the mice were
exposed to deep burn and then the tissue sections at wound sites were collected 21 d after the burn. (C) IF was used to detect
the pan-cytokeratin (Pan-CK) and Y-FISH was used to reveal the Y chromosomeepositive cells. Bar, 75 mm. (D) Wound size
was measured. (E) Alteration of the wound size shown by in vivo fluorescence imaging.
j o u r n a l o f s u r g i c a l r e s e a r c h -- ( 2 0 1 3 ) e 1ee 8 e7
of BM-MSCs in the healing of burn wounds in vivo. In our study,
we demonstrated that the expression levels of CXCL12 and
CXCR4 proteins at the injured sites of BM-MSC-treated mice
afteraburn increasedsignificantlypostburnandreachedapeak
at 7 d post burn. However, the CXCR4-selective antagonist
AMD3100significantly inhibited themobilizationofBM-MSCsto
the wounded skin, therefore prolonging the wound closure.
These data demonstrated that CXCL12/CXCR4 signaling medi-
ated the mobilization of murine BM-MSCs to wound sites for
participation in the wound repair process.
In conclusion, we showed that the BM-MSCs migrated to
the injured sites and localized in the epidermis and hair
follicles of the burned skin. They significantly enhanced burn
wound healing by epithelialization, and the mobilization of
the BM-MSCs was mediated by CXCL12/CXCR4 signaling.
Thus, our data suggest that administration of MSCs to the
injured wound in a proper manner and that the enhancement
of CXCL12/CXCR4 axis would be novel therapeutic strategies
for the treatment of burn wounds.
Acknowledgment
This study was supported by a grant from the National Nature
Science Foundation of China (NSFC30772252) and Science
Fund from the State Key Laboratory (SKLKF 200923).
Supplementary Data
Supplementarydata associatedwith this article canbe found in
the online version at http://dx.doi.org/10.1016/j.jss.2013.01.019.
j o u rn a l o f s u r g i c a l r e s e a r c h -- ( 2 0 1 3 ) e 1ee 8e8
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