J South Med Univ, 2014, 34(4): 441-447

doi 10.3969/j.issn.1673-4254.2014.04.01

441

Original Article

Human umbilical cord-derived mesenchymal stem cells inhibit

proliferation but maintain survival of Jurkat leukemia cells in
vitro by activating Notch signaling
YUAN Yin1, CHEN Danliang2, CHEN Xuan1, SHAO Hongwei1, HUANG Shulin1*
School of Biosciences and Biopharmaceutics, Guangdong Province Key Laboratory for Biotechnology Drug Candidates, Guangdong

Pharmaceutical University, Guangzhou 510006, China; 2Department of Gynecology and Obstetrics, First Affiliated Hospital of Jinan
University, Guangzhou 510630, China

Abstract: Objective To investigate the effects of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on the
proliferation and survival of Jurkat leukemia cells in vitro and explore the possible mechanism. Methods Jurkat leukemia cells
were co-cultured with hUC-MSCs isolated from human umbilical cord tissues by plastic adherence at a ratio of 101. The
proliferation and survival of the co-cultured Jurkat cells, separated by immunomagnetic bead cell sorting on day 4, were
evaluated by flow cytometry. Western blotting was performed to evaluate the activation of Notch signaling in the co-cultured
Jurkat cells. Results Jurkat leukemia cells co-cultured with hUC-MSCs for 4 days showed a lowered proliferation rate and cell
cycle arrest at G0/G1 phase with a reduction in the cell apoptotic rate. Notch signaling pathway was activated in the co-cultured
Jurkat cells as evidenced by an increased cellular expression of HES-1. Conclusion Co-culture with hUC-MSCs can inhibit the
proliferation of Jurkat leukemia cells in vitro and protect the cells from apoptosis by activating Notch signaling, indicating a
potential shielding effect of MSCs on leukemia cells.
Key words: mesenchymal stem cells; umbilical cord; leukemia; proliferation; Notch signaling

INTRODUCTION
Mesenchymal stem cells (MSCs) are nonhematopoietic progenitor cells first isolated from bone
marrow over 40 years ago 1. These cells possess a
profound immunosuppressive activity by modulating the
functions of immune cells through a variety of
mechanisms 2-4. Such unique immunological properties
of MSCs, combined with their hematopoiesis-supportive
function, have caused great enthusiasm about their
potential for treatment of hematological malignancy and
other disorders5, 6. Preliminary studies suggested that
co-infusion of MSCs could reduce the incidence of
graft-versus-host disease as well as promoting engraftment in patients undergoing hematopoietic stem cell
(HSC) transplantation for hematologic malignancy7, 8.
In recent years, ex vivo expanded MSCs from other
tissues, such as umbilical cord, have been actively
investigated. Human umbilical cord-derived MSCs
(hUC-MSCs) have several advantages over bone
marrow-derived MSCs (BM-MSCs), such as a lower risk
of viral contamination, painless collection procedures,
better expandability, and possible source for autologous
Received: 2013-09-23
Accepted: 2013-10-23
Supported by National "Key New Drug Creation" Special and
Major Project (2009ZX09103-708), National Natural Science
Foundation of China (31100664, 31300737, 81303292) and Medical
Scientific Research Foundation of Guangdong Province (B2013197).
*Corresponding author: HUANG Shulin, Professor, E-mail:
shlinhuang@sina.com

cell therapy 9. However, cell-based therapy often

requires large unphysiological numbers of MSCs for
achieving a clinical efficacy, and there is evidence that
co-transplantation of BM-MSCs and HSCs increased the
risk of hematological malignancy relapse 10. In this
context, the potential influences of hUC-MSCs on
hematologic malignant cells have to be evaluated in
preclinical models before it can be used in clinical trials.
T-cell acute lymphoblastic leukemia (T-ALL) is
one of the aggressive hematological malignancies,
constituting a large proportion of acute lymphoblastic
leukemia (ALL) both in children and in adults11. It is
reported that Notch signaling is implicated in the
pathogenesis of T-ALL12, 13. T-ALL patients commonly
have mutations in Notch1, one of the mammalian Notch
signaling receptors, to cause the overactivation of Notch
signaling in T-ALL cells 14. In this study, we
investigated the influence of co-culture with hUC-MSCs
on the proliferation as well as survival of Jurkat T-ALL
cell line in vitro, and explored the possible mechanism
involving Notch signaling to provide further insight into
the biological role of hUC-MSCs for their potential
clinical applications.
MATERIALS AND METHODS
Cell line
Human T-ALL cell line Jurkat (CD4 + , clone E6-1)

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J South Med Univ, 2014, 34(4): 441-447

purchased from the cell bank of Chinese Academy of

Sciences (Shanghai, China) were grown in suspension in
RPMI 1640 medium (Gibco BRL, Grand Island, NY,
USA) supplemented with 10% fetal bovine serum (FBS;
Sijiqing, Hangzhou, China) and 1% penicillin/
streptomycin (Gibco BRL). The cells were incubated at
37 in a humidified atmosphere of 5% CO2 and
passaged every 2 days to maintain a cell density in the
culture not exceeding 1106 cells/ml.
Isolation and expansion of hUC-MSCs
Umbilical cord tissues from full-term healthy
neonates were collected immediately upon delivery with
informed consent from the donor, and stored in PBS
supplemented with 1% penicillin/streptomycin before
processing. The hUC-MSCs were isolated by direct
plastic adherence method without enzymatic digestions.
Briefly, the umbilical cord sample was cut into segments
2-3 cm long and the residual cord blood and blood
vessels (two arteries and one vein) were removed. The
tissue blocks were then minced into 1-2 mm3 fragments
and plated separately in 6-cm polystyrene tissue culture
dishes pre-coated with FBS. After the dishes were kept
inverted for 20 min, growth medium [DMEM/F12
medium (Gibco BRL) supplemented with 10% FBS and
1% penicillin/streptomycin] was added carefully. The
cultures were maintained at 37 in a humidified
atmosphere containing 5% CO2. On day 7, the nonadherent tissue fragments were removed by changing the
medium. The culture medium was changed every 3 to 4
days thereafter. Approximately 3 weeks later, the welldeveloped colonies of fibroblast-like cells (80%-90%
confluent) were harvested with 0.25% trypsin (Gibco
BRL). The harvested cells were passed through a
100-m sterile mesh and then seeded in larger flasks for
further expansion. The cells at passage 4 to 8 that
displayed a homogeneous MSC phenotype were used for
experiments.
Co-culture of hUC-MSCs and leukemia cells
The hUC-MSCs were plated in 6-well plate at 2
105 per well and allowed to adhere at 37 for 24 h.
Jurkat leukemia cells were then inoculated in
suspension or on the hUC-MSCs monolayer at a ratio of
101, and on day 4, the co-cultured Jurkat cells were
separated from hUC-MSCs by careful pipetting with
ice-cold PBS as previously described15. To eliminate
possible contamination with hUC-MSCs fraction, the
collected Jurkat cells were further purified using CD4 +
magnetic micro beads according to manufacturer's
instructions (Miltenyi Biotec, Bergisch Gladbach,
Germany).
Cell proliferation assays
The proliferation of Jurkat leukemia cells was
assessed by two different methods. For cell cycle
analysis, Jurkat cells fixed in 70% ethanol overnight at
4 were treated with 10 g/ml RNase A (Sigma, St.
Louis, MO, USA) and then stained with 50 g/ml

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propidium iodide (PI; Sigma) at room temperature for 30

min. Following staining, the cellular DNA content was
immediately analyzed on a Gallios flow cytometer
(Beckman Coulter, Brea, CA, USA). Alternatively, the
cell proliferation was detected by carboxy fluorescein
diacetate succinimidyl ester (CFSE; eBioscience, San
Diego, CA, USA) labeling following the manufacturer's
instructions. The cell cycle distribution and cell
generations were determined using ModFit software
(Verity Software House, Topsham, ME, USA).
Cell apoptosis analysis
The cell apoptosis was analyzed using the
MEBCYTO apoptosis kit (MBL, Nagoya, Japan). Jurkat
cells were washed once with PBS and resuspended in 85
l binding buffer, followed by incubation with 10 l
Annexin V-FITC and 5 l PI at room temperature for 15
min in the dark. After incubation, 400 l of binding
buffer was added. The cell samples were then measured
by flow cytometry.
Detection of Notch signaling molecules
The expressions of Notch signaling molecules on
Jurkat cells and hUC-MSCs, including the Notch1
receptor and one of its ligand, Jagged1, were confirmed
by flow cytometry. The monoclonal antibodies used
included phycoerythrin (PE)-conjugated anti-Notch1
(R&D systems, Minneapolis, MN) and carboxyfluorescein (CFS)-conjugated anti-Jagged1 (R&D
systems). The intracellular level of HES-1, a classic
transcriptional target of Notch signaling, was examined
by Western blotting following standard procedures. In
brief, the cells (106) were lysed in RIPA lysis buffer
according to the manufacturers instructions (Beyotime,
Haimen, China). Equal amounts of protein from each
culture were loaded on polyacrylamide gels followed by
transfer to polyvinylidene difluoride (PVDF) membranes
(Bio-Rad, Hercules, CA). The membranes were treated
with rabbit anti-human HES-1 at 11000 (Epitomics,
Burlingame, CA, USA) or with anti-GAPDH (Goodhere
Biotechnology, Hangzhou, China) and then with antirabbit horseradish peroxidase (HRP)-conjugated secondary antibody (15000, ZSGB-Bio, Beijing, China).
The protein bands were developed by chemiluminescence.
Statistical analysis
Statistical comparisons were carried out using the
GraphPad Prism software. The data were presented as
MeanSD. When applicable, Student's t-test was used to
examine the differences between groups. Differences
were considered statistically significant for a P value
less than 0.05.
RESULTS
Characterization of hUC-MSCs
MSCs were successfully isolated from human

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J South Med Univ, 2014, 34(4): 441-447

umbilical cord tissues by direct plastic adherent

method. Fibroblast-like cells around the umbilical cord
tissue fragments were observed as early as 2 weeks of
culture (Fig.1A). These cells formed whirlpool-like

arrays when a confluent monolayer was developed

(Fig.1B), and showed a good homogeneity. The cells
expressed MSC markers CD73, CD90, and CD105, but
were negative for CD34 and CD45 (data not shown).

Fig.1 Morphological features of hUC-MSCs and Jurkat leukemia cells under inverted microscope (Original magnification:
100). A: hUC-MSCs in primary culture. The black arrow indicates part of the adherent umbilical cord tissue fragment; B:
The confluent state of hUC-MSCs in subcultivation; C: Jurkat cells grown on hUC-MSC monolayer in the co-culture system.

hUC-MSCs inhibited Jurkat cell proliferation

We studied the influence of hUC-MSCs on the
proliferative activity of Jurkat leukemia cells in
co-culture. The spatial relationship of Jurkat cells and
hUC-MSCs in the co-culture system was shown in
Fig.1C. Cell cycle analysis revealed a marked arrest in
cell cycle progression, characterized by a decrease of
proliferating cells (S and G2/M) and an accumulation of
cells in G0/G1 in Jurkat cells grown on hUC-MSCs as
A

G0/G1: 56.63.6
S: 35.04.9
G2/M: 8.53.1

50
100 150
200
PI fluorescence intensity

100%

G2/M
S
G0/G1

80%
60%
40%
20%
0%

300

Number
600 900

G0/G1: 39.73.7
S: 43.73.0
G2/M: 16.64.2

On MSCs
Number
300 600 900 200

1200

In suspension

compared with Jurkat cells cultured alone (Fig.2). The

inhibitory effect of hUC-MSCs on Jurkat cells was
further confirmed by cell division analysis using CFSE
labeling. As shown in Fig.3, 27.57% of Jurkat cells
cultured in suspension were already in the 7th
generation, while most of the hUC-MSC-supported
Jurkat cells (54.16% ) remained in the 6th generation
and there were scarcely cells of the 7th generation,
indicating a decreased proliferation of Jurkat cells in
contact with hUC-MSCs.

50
100 150
200
PI fluorescence intensity

In suspension

On MSCs

Fig.2 Influence of hUC-MSCs on cell cycle distribution of Jurkat leukemia cells. A: Jurkat cells cultured with or without hUC-MSCs
were analyzed for cell cycle progression. Results shown are representative histograms of 3 independent experiments. Percentages
of cells in each phase are shown in the upper corner of each cell-cycle graph. B: Cell cycle fractions of 3 independent
measurements. In suspension: Jurkat cells cultured alone; On MSCs: Jurkat cells cultured on hUC-MSCs.

hUC-MSCs suppressed Jurkat cell apoptosis

To investigate whether hUC-MSC-mediated
proliferation inhibition was associated with the
induction of apoptosis, we examined the influence of
hUC-MSCs on the survival of Jurkat cells by Annexin-V
and PI staining. When maintained for 4 consecutive

days without changing or supplementing growth

medium, Jurkat cells exhibited spontaneous apoptotic
features (Fig.4A), while those grown on hUC-MSCs
showed a reduction in cell apoptosis by approximately
50% (Fig.4). These data suggest that hUC-MSCs
mediated the growth arrest of Jurkat cells without
inducing their apoptosis and maintained their viability.

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In suspension

On MSCs

Parent
Generation 2
Generation 3
Generation 4
Generation 5
Generation 6
Generation 7
Generation 8
Generation 9
Generation 10

240

240

320

320

54.16%

80

160

160

Number

27.57%

80

Number

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50

100
150
Channel (CFSE)

200

50

100
150
Channel (CFSE)

200

Fig.3 Generation assay of Jurkat leukemia cells labeled with CFSE. Histogram deconvolution based on CFSE
fluorescence data were performed by ModFit software.

In suspension
10

On MSCs

10

102

PI

PI

102

101

101
11.5

100

5.6

100

3.1
100

101
102
Annexin V

2.3

103

100

101
102
Annexin V

103

30

Mean apoptosis (%)

P=0.3

20

10

0
In suspension

On MSCs

Fig.4 Influence of hUC-MSCs on spontaneous apoptosis of Jurkat leukemia cells evaluated by

annexin V staining and propidium iodide (PI) incorporation. A: Flow cytometry profiles of one
representative experiment; B: Percentage of apoptotic cells of 3 separate experiments. The
presence of hUC-MSCs protected Jurkat cells from apoptosis (P<0.05).

Notch signaling is activated in Jurkat cells co-cultured

with hUC-MSCs
To further explore the molecular mechanism for the

above observation, we examined Notch signaling in the

cells, given its roles in regulating cell proliferation and
apoptosis. As Notch signaling pathway is mainly
triggered by Notch receptor/ligand interactions through

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direct cell-cell contact, we first evaluated the presence

of specific Notch family members on hUC-MSCs and
Jurkat cells. Flow cytometry detected Notch1 receptor
on Jurkat cells, and the hUC-MSCs expressed a
moderate level of Jagged1 (Fig.5A), indicating the
capacity of hUC-MSCs to trigger Notch signaling in

Jurkat cells. We also assayed the expression of HES-1, a

classic transcriptional target of Notch signaling. HES-1
was constitutively expressed in Jurkat cells, and the
direct contact with hUC-MSCs resulted in an increased
expression of HES-1 in Jurkat cells as expected (Fig.5B
and 5C).

Events

A
100

100

80

80

60

60

40

40

20

20

0
102

103
104
Jagged1 (hUC-MSCs)

102

105

C
On MSCs

HES-1/GAPDH

105

0.8
HES-1

GAPDH

Relative expression

In suspension

1.0

103
104
Notch1 (Jurkat)

0.6
0.4
0.2
0.0
In suspension

On MSCs

Fig.5 Involvement of Notch signaling in the interaction between Jurkat leukemia cells and hUC-MSCs. A: Notch1 and
its ligand Jagged1 were expressed on Jurkat cells and hUC-MSCs, respectively. Open histograms: Isotype control;
Filled histograms: Cells labeled with specific monoclonal antibodies. B: Western blotting showing up-regulation of
HES-1 protein in Jurkat leukemia cells following contact with hUC-MSCs. C: Relative expression of HES-1 protein in
Jurkat cells from different cultures determined by Western blotting (Mean SD, n=3). HES-1 protein levels were
quantified and normalized for GAPDH expression. *P<0.05 vs Jurkat cells cultured alone in suspension.

DISCUSSION
Mesenchymal stem cells (MSCs) are nonhematopoietic stem cells that can be isolated from a
variety of tissues, most commonly from the bone marrow
(BM). However, aspiration of BM involves invasive
procedures, and the yield of bone marrow-derived MSCs
decreases significantly with the donor's age 16.
Therefore, the search for alternative sources of MSCs is
of significant value. MSCs from umbilical cord have in
recent years become a new focus in stem cell research
due to their attractive features.
Similar to BM-MSCs, hUC-MSCs also exhibit a low

immunogenicity17, 18, suggesting their potential applicability in allogeneic HSC transplantations. However,
considering the emerging evidence that bone
marrow-derived MSCs may increase the risk of cancer
relapse10, 19, it is still necessary to evaluate the efficacy
and safety of hUC-MSCs before it could be applied in
clinical trials.
In the present study, we prepared MSCs from
human umbilical cord tissues and utilized a co-culture
system to evaluate their impact on Jurkat T-ALL cell
line. Our data showed that hUC-MSCs had a dual
function in vitro: they inhibited the proliferation of
Jurkat cells and also prevented their death. A possible

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relationship is indicated between hUC-MSC-induced

proliferation inhibition and the survival of Jurkat cells.
It was inferred that proliferation inhibition could confer
cancer cells a better survival because proliferating cells
are more vulnerable to apoptotic stimuli 20. This
mechanism can preserve the self-renewal ability of
cancer cells and thus sustain the malignant process.
Therefore, the clinical use of MSCs for malignant
conditions should be handled with extreme caution21.
To further explore the underlying mechanism, we
examined Notch signaling in co-cultured Jurkat cells
due to its involvement in the pathogenesis of T-ALL12, 13
and its critical role in rescuing cells from apoptosis 22, 23.
Notch pathway is evolutionarily conserved and plays a
key role in cell fate determination in many tissues13, 24.
The activation of Notch signaling depends on direct cellcell contact. The binding of Notch receptor with its
ligand on neighboring cells triggers proteolytic cleavage
and release of the intracellular domain of Notch
receptor, which enters the cell nucleus and regulates the
downstream target genes, such as Hes-1 and Deltex-113,
25
. Our results showed that Jurkat T-ALL cell line
constitutively expressed Notch1 receptor as well as its
target HES-1, and the level of Notch activation in Jurkat
cells was further elevated following contact with
hUC-MSCs, which may account for the anti-apoptotic
effect of hUC-MSCs in Jurkat leukemia cells. On the
other hand, Jagged1, one of the Notch ligands, was
found to be expressed by hUC-MSCs. Jagged1 is a
membrane-spanning protein with a large extracellular
domain for Notch receptor binding 26. Therefore, the
hUC-MSCs were able to initiate the stimulation of Notch
signaling in Jurkat leukemia cells through the
interaction between their Jagged1 ligand and the Notch1
receptor on Jurkat cells. It has been reported that
Jagged1-mediated Notch signaling is involved in the
suppressive effect of BM-MSCs on immune cells27, and
MSC-derived osteoblasts regulate the HSC niche by
using the same Jagged1/Notch system 28. Besides,
Jagged1 was also found necessary for the expression of
various smooth muscle markers during differentiation of
MSCs into smooth muscle cells29.
Overall, we observed anti-proliferation as well as
anti-apoptotic effects of hUC-MSCs on Jurkat leukemia
cells at the same time. Although the anti-proliferation
effect might have therapeutic implications, the
anti-apoptotic effect constitutes a potential side effect of
ex vivo expanded hUC-MSCs, which might maintain
residual leukemia cells and lead to disease recurrence.
Therefore, the exploitation of MSCs in new therapeutic
strategies should be cautious for malignant conditions.
Our results also point to the crucial role of Notch
signaling in the hUC-MSC-induced influence on Jurkat
leukemia cells, indicating its role as a potential target
for the reversion of MSC-mediated protection on T-ALL
leukemia cells.
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// 5100062
510630

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2013-09-23
2009ZX09103-708311006643130073781303292
B2013197
E-mail: yinyinyuan@126.com
E-mail: shlinhuang@sina.com