Telomere and Telomerase 2016; 3: e1184. doi: 10.14800/tt.1184; 2016 by Drenka Trivanovi, et al.

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RESEARCH HIGHLIGHT

Correlation between telomere maintenance and stemness of

mesenchymal stem/stromal cells
Drenka Trivanovi1, Jelena Krsti1, Aleksandra Jaukovi1, Branka Popovi2, Ivana Oki Djordjevi1, Tamara Kukolj1,
Hristina Obradovi1, Slavko Mojsilovi1, Juan Francisco Santibanez1, Diana Bugarski1
1

Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, 11129 Belgrade,
Serbia
2
Institute of Human Genetics, School of Dentistry, University of Belgrade, 11129 Belgrade, Serbia
Correspondence: Drenka Trivanovi
E-mail: drenka.trivanovic@imi.bg.ac.rs
Received: January 10, 2016
Published online: February 16, 2016

Tissue regeneration and repair is strongly dependent on resident stem cells behavior and functionality.
Telomeres and telomerase are known to be regulators of stem cell self-renewal, controlling their cell cycle, thus
determining their replicative potential. Also, telomeres and telomerase are involved in regulation of
differentiation progress of stem cells, although these effects are poorly understood. In previously published
study, we compared relative telomere length (RTL) and hTERT mRNA expression in mesenchymal
stem/stromal cells (MSCs) isolated from: peripheral blood (PB-MSCs), umbilical cord (UC-MSCs), exfoliated
deciduous teeth (SHEDs), periodontal ligament (PDL-MSCs) and adipose tissue (AT-MSCs), in context of their
proliferation and differentiation. We found that PB-MSCs and UC-MSCs demonstrated the highest RTL and
hTERT mRNA expression, accompanied with their higher proliferation capacity and adipogenic differentiation
in comparison with other MSCs. On the other hand, SHEDs, PDL-MSCs and AT-MSCs demonstrated lower
RTL value and hTERT mRNA expression accompanied with higher osteogenic differentiation capacity and
higher expression of pluripotency markers (Nanog, Oct-4A, Oct-4B and SOX-2) mRNA, when compared to
PB-MSCs and UC-MSCs. These results highlighted the difference between MSCs isolated from various tissues
with indications that telomere status might be one of the predictable factors for their stemness and functionality,
prior to their potential application in cell-based therapy.
Keywords: mesenchymal stem/stromal cell; telomere, stemness; proliferation; pluripotency markers
To cite this article: Drenka Trivanovi, et al. Correlation between telomere maintenance and stemness of mesenchymal
stem/stromal cells. Telomere Telomerase 2016; 3: e1184. doi: 10.14800/tt.1184.
Copyright: 2016 The Authors. Licensed under a Creative Commons Attribution 4.0 International License which allows
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transform, and build upon the material for any purpose, even commercially, as long as the author and original source are
properly cited or credited.

Tissue development is governed by dynamic equipoise of

senescence and apoptosis of terminally differentiated cells on
one side, and appropriate gradual differentiation of rare
resident stem or progenitor cells in tissues on the other side.
These processes require strict control of cell-cycle
progression, followed by DNA replication, which are

conditioned by chromosome stability provided by telomere

replication and telomerase-mediated telomere extension in S
phase. Due to the role in cell-cycle control and genome
stability, telomere status is an important feature of stem,
progenitor or precursor cells involved in maintenance of
tissue homeostasis [1, 2].

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Telomere and Telomerase 2016; 3: e1184. doi: 10.14800/tt.1184; 2016 by Drenka Trivanovi, et al.
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In short, telomeres protect DNA ends present at the

termini of linear chromosome, prevent broken ends to act, by
inhibiting telomere fusions, illegitimate recombination, and
genomic instability, which could lead to cellular
transformation [3, 4]. Telomeric DNA acts with
telomere-associated proteins to form additional structures
(such as G-quadruplexes and T-loops) and in some regions
double-stranded DNA (the D-loop) which are responsible for
the prevention of the irregular activation of checkpoints and
DNA repair response at chromosome ends [5, 6].
About 50 bp of telomeric repeats are lost per generation
(division), due to inability of the semiconservative DNA
replication to replicate the entire telomere [7]. Telomere
maintenance
requires
telomerase,
network
of
telomere-associated proteins such as telosome and shelterin,
and also the inhibited DNA-damage response signals that
include ATM and ATR pathways, homologous
recombination, and non-homologous end joining [6]. Repair
response could also activate alternative mechanisms of
telomere lengthening (ALT), contributing to the capacity of
transformed cells to gain infinite growth capacity [5].
Telomerase is a ribonucleoprotein complex and acts as a
reverse transcriptase, which compensates telomere loss, as
well as loss accomplished by nucleolytic processing, by
catalyzing the addition of telomeric hexanucleotide repeats
onto the 3 end of the chromosome [7]. Telomerase consists
of the telomerase reverse transcriptase (TERT) and
telomerase RNA component (TERC) as the template for
telomere extension during addition of TTAGGG repeats onto
chromosome ends. Contrary to ubiquitous TERC expression,
expression of TERT is highly regulated. Although TERT
expression and telomerase activity are hardly detectable in
somatic cells, telomerase is expressed in stem cells and
highly expressed in cancer cells [6].
Telomere biology became a field that holds great promise
for medicine, particularly for aging and age-related diseases,
including diabetes mellitus, cardiovascular diseases, liver
disorders and cancer, and their status in stem cells as
compartments which contribute to tissue homeostasis
obtained particular attention [8].
Importance of Telomere Maintenance for Stem Cell
Properties
Pluripotent stem cells (PSCs), including embryonic stem
cells (ESCs) and engineering-derived induced pluripotent
stem cells (iPSCs), have the potential to produce any type of
cells from all three basic germ layers and the capacity to
self-renew and proliferate indefinitely in vitro, and therefore
hold unrivaled promise for regenerative medicine. Based on
previous data that demonstrated a crucial role of

overexpressed TERT in the generation of iPSCs [9, 10], it is

suggested that telomerase has major role in reprogramming,
self-renewal and maintenance of iPSCs pluripotency [11].
Except stem cells and lymphocytes, most human somatic
cells gain abolished telomerase activity after birth. The level
of telomerase is low in the majority of human adult stem
cells, except in cells that undergo rapid expansion, such as
committed hematopoietic progenitor cells [12], activated
lymphocytes [13], or keratinocytes [14, 15, 16, 17]. Tissue resident
stem cells are present in almost all tissues, and therefore
represent the most investigated primary stem cells. Due to
their availability and abundance in various adult or
birth-associated tissues they take important place in
regenerative medicine approaches.
Since scarce populations of hematopoietic stem cells
(HSCs) have the ability to repopulate myeloablated bone
marrow, it is suggested that these cells possess extensive
replicative capacity. Besides this feature of HSCs
demonstrated both in laboratory and in clinical settings, it
was described that their replicative capacity is limited and
dependent on telomere shortening [18]. Cautions about
telomere length of HSCs are related to their application in
HSCs transplantation (HSCT). It is shown that cells from old
donors or patients with telomerase deficiencies had limited
replication ability, rendering the cell number necessary for
HSCT insufficient [19]. Moreover, in patients who had
received HSCT, the telomere length of engrafted stem cells is
closely related to the outcomes of transplantation, thus
highlighting the significance of telomere status during donor
selection [20]. Therefore, some authors speculate about
advantages of cord blood HSCs use, which are related to
longer telomeres and higher replication ability than HSCs in
bone marrow [19]. Telomere shortening in HSCs is considered
to be a risk factor that contributes to the development of
chromosomal instability and malignant transformation. In
agreement with this hypothesis, telomere shortening in
patients with dyskeratosis congenita correlates with an
increased risk of hematological neoplasms [15, 21].
As already mentioned, mesenchymal stem/stromal cells
(MSCs) have been isolated from many different
birth-associated or adult tissues: e.g. umbilical cord, amniotic
fluid, placenta, bone marrow, adipose tissue, peripheral
blood, urine, dental tissues, synovial fluid, dermis, muscle
etc [22].
Thanks to their availability in various adult tissues, MSCs
represent a promising tool for cell-based therapies because of
their self-renewal capacity and multipotent differentiation
capacity. However, for their application in experimental or
clinical settings, a great number of MSCs is necessary, thus

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Telomere and Telomerase 2016; 3: e1184. doi: 10.14800/tt.1184; 2016 by Drenka Trivanovi, et al.
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presenting a challenge in laboratory conditions which are

often related to disrupted functionality of MSCs. Previously,
it has been shown that bone marrow MSCs loose replication
capacity and differentiation potential during two months of in
vitro cultivation [23]. There are opposite data about effects of
extensive ex vivo expansion of MSCs in laboratories on their
biology, where although a risk of malignant transformations
was suggested [2], there is evidence that long term cultivation
of MSCs could not lead to transformation, because MSCs
are not able to escape senescence [17, 24, 25]. Importantly,
recent data showed a key role of telomere status in HSCs and
bone marrow MSCs for the development of
dyskeratosis congenita, a condition where shortened
telomeres not only in HSCs, but also in bone marrow MSCs
lead to disease development. This study demonstrated that
shortened telomeres are involved in altered colony forming
ability, differentiation capacity and hematopoiesis supporting
role of bone marrow MSCs [26].
Research Highlights
It is known that telomeres shorten during cultivation of
MSCs, leading to cellular senescence and decreased
proliferation rate, accompanied with shift of telomere to the
nuclear center [27]. In our previously published study, we
compared properties of cells isolated from human tissues:
umbilical cord (UC-MSCs), peripheral blood (PB-MSCs),
exfoliated deciduous teeth (SHEDs), periodontal ligament
(PDL-MSCs) and adipose tissue (AT-MSCs) [28]. In the first
step, our results demonstrated that all types of cells expressed
mesenchymal CD markers: CD90, CD105, CD44 and CD73,
while hematopoietic CD34 and CD45 were not expressed.
Additionally, all types of isolated cells demonstrated capacity
for colony forming in CFU-F assay. However, capacity for
CFU-F forming varied: PB-MSCs (n65), UC-MSCs (n60),
SHEDs (n38), PDLMSCs (n10), AT-MSCs (n10), thus
indicating a potential difference in their self-renewal
capacity.
Besides various CFU-F efficiencies, in our study isolated
cells demonstrated significantly different proliferative
capacities. UC-MSCs and PB-MSCs demonstrated the
highest proliferation rate, while PDL-MSCs and AT-MSCs
showed the lowest. In accordance with their proliferation and
population doublings, isolated cells showed different relative
telomere lengths (RTL) when they were compared in same
passage. PB-MSCs showed the highest RTL, which was in
accordance with their highest proliferation capacity. On the
other hand, AT-MSCs showed the lowest RTL value, which
was in accordance with their lowest proliferation rate.
SHEDs and PDL-MSCs showed higher RTL values that
AT-MSCs, but lower than in PB-MSC and UC-MSCs.
However, although UC-MSCs showed high proliferation

capacity, they had lower RTL value than PB-MSCs. Also, a

similar trend was observed in RTL values between isolated
cell populations, to that in CFU-F efficiency. Therefore, we
can suppose that telomere status of isolated cells was the
cause of their CFU-F efficiency and replicative potential, as
previously suggested for bone marrow MSCs [29] and
AT-MSCs [30].
Moreover, we investigated hTERT mRNA expression in
all isolated cell populations. Obtained results showed that
UC-MSCs and PB-MSCs expressed the highest level of
hTERT mRNA in comparison to other cells. Interestingly,
PDL-MSCs and AT-MSCs showed higher hTERT mRNA
expression than SHEDs. Expression of hTERT mRNA was
proposed as a predictive marker of telomerase activity [6].
Although we could not conclude that PDL-MSCs and
AT-MSCs had higher telomerase activity, we can suppose
that this level of hTERT mRNA expression was not
sufficient to maintain telomere length in these cells, which
finally contributed to their low replicative capacity.
It can also be speculated that the difference observed in
telomere length and hTERT expression can be explained by
different maturity of isolated cells. In addition, we want to
point out that their differences could be related to
tissue-origin, donor age and behavior of cells in vitro.
Moreover, heterogeneity of isolated MSCs populations
derived from adult tissues make comparison of their
properties even more difficult [31].
As the regenerative potential of MSCs rests on their ability
to generate mature cell types through processes of
differentiation, these adult stem cell populations might also
exhibit similar heterogeneity within their primitive
compartments.
To confirm their mesenchymal stem/stromal-like nature,
we investigated differentiation ability of isolated cells. Our
results confirmed tri-lineage differentiation capacity of all
isolated cells. Interestingly, we also observed spontaneous
differentiation of isolated cells. PB-MSCs and UC-MSCs
showed spontaneous adipogenic differentiation while SHEDs
and PDL-MSCs demonstrated sponotaneous osteogenic
differentiation.
AT-MSCs
showed
spontaneous
differentiation of both. However, besides the highest RTL
value and hTERT mRNA expression, PB-MSCs and
UC-MSCs showed highest expression of PPAR mRNA,
major transcription factor of adipogenesis. Contrary, SHEDs,
PDL-MSCs and AT-MSCs, possessed lower RTL values and
hTERT mRNA expression, but higher expression of Cbfa1,
major transcriptional factor of osteogenesis. Negative
correlation between expression of Cbfa1 and TERT was also
described in human bone marrow [32] and placental MSCs [33].

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Telomere and Telomerase 2016; 3: e1184. doi: 10.14800/tt.1184; 2016 by Drenka Trivanovi, et al.
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Although spontaneous differentiation of MSCs in cell culture

conditions is an undesirable feature, some studies have
shown that MSCs can undergo spontaneous differentiation
[34] or transformation [17] during culturing. However, whether
observed spontaneous differentiation is a consequence of
heterogeneity of isolated MSCs or an artifact of in vitro
cultivation, needs to be further elucidated.

telomerase-mediated
functions.

Moreover, our results showed that SHEDs, PDL-MSCs

and AT-MSCs, possessed lower mRNA expression for
TERT, but higher expression of pluripotency markers mRNA
(Nanog, Oct-4A and B, SOX-2) than PB-MSCs and
UC-MSCs. Contrary, in previous study, hTERT has been
proposed to have a role in the upregulation of pluripotency
marker expression in MSCs [35]. Although expression of
pluripotency markers in adult stem cells is demonstrated in
many studies [33, 36], their role is still not well defined. In
some studies, pluripotency marker expression was shown to
be related to MSCs stemness and undifferentiated status
maintenance [37], while other studies showed their
overexpression was related to enhanced differentiation of
MSCs [36, 38]. This complexity is probably a consequence of
questionable expression of pluripotency markers in MSCs,
because these markers, such as Oct4 possess several
pseudogenes which share high sequence homology to
Oct-4A [39] and have non-pluripotency activities. This
discrepancy within expression of TERT, pluripotency
markers and differentiation of MSCs opens many questions
regarding the role of telomeres and telomerase in the
regulation of stemness and functionality of MSCs.

Acknowledgments

Conclusions
Our study drew attention to possibility that MSCs, possess
and reserve tissue origin-related individualities, which affect
their native and in vitro stem-cell-like features. Although
cells isolated from various tissues fulfilled the criteria for
MSCs characterization and displayed similar phenotypes,
they exhibited high degree of variability in their RTL and
hTERT mRNA expression. This variability was in line with
their replication and clonogenic capacity. Moreover, our
study showed that MSCs with higher RTL and hTERT
mRNA expression had higher spontaneous adipogenesis
level, contrary to those which had lower telomere lengths and
hTERT mRNA expression and demonstrated spontaneous
osteogenesis ability. Our results led us to conclude that
telomere status can be predictable factor in the evaluation of
replication and self-renewal capacity of MSCs. It is possible
to speculate that telomere and telomerase status in MSCs
could control stemness of these cells, by regulating
expression of pluripotency markers and differentiation
processes. However, more detailed studies are necessary to
fully reveal molecular mechanisms involved in telomere- and

effects

on

MSCs

behavior

and

Conflicting interests
The authors have declared that no conflict of interests
exist.

This study was supported by grant #175062 from the

Ministry of Education, Science and Technological
Development of Republic of Serbia.
Authors contribution
D.T. and A.J. conceived the idea and experimental design.
J.K. and D.B. helped writing the text. B.P., I.O.DJ., S.M.,
T.K., H.O. and J.F.S provided their excellent scientific
suggestions.
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