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Embryonic Stem Cells (ESCs) constitute a
small elite group of immortal cells with specific biological mission and
mechanisms of rejuvenation, self-renewal and maintenance. Successes in nuclear
reprogramming, induced pluripotency and other related protocols make these
naturally pluripotent cells “gold standard” for comparison, understanding the
basic mechanisms of pluripotency and for development of new biotechnologies.
Here, we briefly addressed three aspects of ESCs biology that could be directly
linked to anti-aging and longevity-promoting interventions: (i) how ESCs
maintain the telomere length and why it is so important for pluripotency; (ii)
paradoxical combination of superior protection of ESCs with hypersensitivity to
apoptosis; and (iii) the role of hypercapnic/hypoxic conditions in ensuring and
keeping the ESC features.
Keywords:
Embryonic stem cells, Pluripotency, Telomeres, Telomerase, Hypoxia, Hypercapnia,
Aging
Abbreviations: ALT: Alternative Lengthening of Telomeres; DSBs: Double Strand
Breaks; ESCs: Embryonic Stem Cells; HSCs: Hematopoietic Stem Cells; iPSCs:
Induced Pluripotent Stem Cells; LUCA: Last Universal Common Ancestor; MSCs: Mesenchymal
Stem Cells; ROS: Reactive Oxygen Species; TERRA RNA: Telomeric Repeat-Containing
RNA; Terc (TERC): Telomere RNA Component: Tert (TERT): Telomerase Reverse
Transcriptase
INTRODUCTION
Embryonic Stem Cells (ESCs) are a gold
standard of cellular pluripotency and immortality. They can generate any cell
of over 200 cell types in our body, known thus far and preserve stable
karyotype, pluripotency, proliferative capacity and telomere length after
hundreds of population doublings during months and years of continuous
maintenance in culture [1-3]. The ever-growing interest to this elite group of
cells in gerontology is primarily supported by the expectations of new
efficient strategies in tissue regeneration and anti-aging. To promote the
study on ESC biology, the NIA Mouse ESC Bank, for example, has generated and
held 185 ESC lines which can be differentiated into various cell types by
specific transcription factors within 48 h [4].
According to intriguing data by Ratajczak et
al. [5-8] adult tissues contain ESC-like pluripotent stem cells as a backup for
the tissue-committed stem cells. Most likely, these quiescent cells are
remnants of ESCs, can be mobilized at stressful conditions to support tissue
repair, and presumably have a role in determination of longevity. Comparison of
several murine strains differing in their lifespan showed that the longer-lived
strains have a more abundant pool of ESC-like cells [6].
Another
important aspect of putative anti-aging effects of ECSs and probably other
pluripotent (e.g. iPSCs) and multipotent (e.g. MSCs) stem cells is that they
may also act in a paracrine manner [9-11]. This gained support from the
observation that ESC-conditioned medium suppressed
Before
deployment of the ambitious perspectives in cellular rejuvenation and tissue
regeneration based on artificial pluripotent cells, it seems relevant studying
as much as possible about their natural counterparts. ESCs could be a perfect
choice to fulfill the task. Unfortunately, the expectations for application of
pluripotent cells in anti-aging, especially in in vivo models [18]
remain insufficiently explored, supporting the contentions of gearing up their
study. Here, we briefly addressed three aspects of ESC biology that could be
directly linked to anti-aging and longevity-promoting interventions: (i) how
ESCs maintain the telomere length and why it is so important for pluripotency;
(ii) paradoxical combination of superior protection of ESCs with
hypersensitivity to apoptosis; and (iii) the role of hypercapnic/hypoxic
conditions in ensuring and keeping the ESC features.
ESCs GET TO THE TOP IN MAINTAINING THE TELOMERE LENGTH
Telomeres
and telomerase
Each end of
a chromosome of eukaryotic organisms contains a special region of
repetitive nucleotide sequences called a telomere. In vertebrates,
telomeric DNA consists of multiple tandem hexomere repeats – GGGATT for the
telomere DNA heavy strand and complementary CCCTAA for the light strand. In
complex with six proteins known as shelterin, non-translating (TERRA) RNA and proteins associated with the heavy
strand overhang, telomeres create a unique telomeric chromatin for protecting
the chromosome ends [19,20]. Telomeres are apparently the most vulnerable
elements of the genome and are prone to attrition (a loss of small fragments of
DNA at each round of replication), because of the DNA incomplete
end-replication problem. Yet, occasional damage to telomeric DNA and especially
breaks of the single-stranded overhangs could be a main cause of telomere
shortening [21]. Overly short or otherwise impaired telomeres could cause
chromosome end-to-end fusion or recombination, thus leading to genome
instability, with far-reaching consequences including tumorigenesis [22,23].
Telomere length
is recovered by a specialized ribozyme – telomerase or by a homologous
recombination known as alternative lengthening of telomeres (ALT). Telomerase
consists of two functionally diverse subunits – reverse transcriptase (Tert)
and telomere RNA template (Terc) [20]. Robust expression of these subunits and
especially Tert, is an important attribute of all unlimitedly proliferating
pluripotent stem cells (except
of early embryo cleavage stages), as they maintain
telomere length mostly through telomerase activity. ALT has primarily been
found in cells with no or very low telomerase activity – in early embryo cleavage stages (when the number of cells
increases without increasing their total mass) [24] and in somatic cells [25].
Telomeres and
telomerase activity in ESCs
Efficient telomere homeostasis is critical
for proper functionality of both embryonic and resident stem cells and therefore
essential for tissue homeostasis throughout the life of an organism [26].
Telomere elongation is crucial for the self-renewal of ESCs [27], while
telomere shortening leads to replicative senescence of their differentiated
progeny and was suggested as one of the hallmarks of aging [13]. The rate of
telomere shortening seems to be in some proportion to the species-specific
longevity. For example, the mouse telomeres shorten 100 times faster than human
telomeres [28].
As could be expected, ESCs have one of the
longest telomeres as compared to other cell types. In humans, telomere size
first decreases in early embryo cleavage stage cells but then reaches its
maximum length in the blastocysts (8.4 kb and 12.2 kb, respectively) [29].
Notably, the elongation of telomeres in the blastocysts is accompanied by a
gradual exacerbation of the intracellular hypoxia/hypercapnia, especially in
ESCs of the inner cell mass of the blastocyst.
The most stringent tests for pluripotency –
generation of complete pups and germline-competent chimeras – showed that only
ESCs with long telomeres possessed authentic developmental pluripotency,
whereas ESCs with short telomeres failed the tests [27]. Additionally, ESCs with
short telomeres exhibited a lower proliferative rate and germ cell
differentiation, as well as a capacity to modify the expression of genes
related to embryogenesis and epigenetics. iPSCs with longer telomeres also were
superior in generating chimeras over the cells with short telomeres, thus
suggesting that telomere length could be a valuable marker of cell pluripotency
[27].
TERT overexpression enhanced telomerase
activity, proliferative rate and colony-forming capacity of human ESCs [30].
Differentiated progeny of TERT-overexpressing ESCs also showed an enhanced
telomerase activity and resistance to oxidative stress, whereas downregulation
of TERT decreased the proliferative rate and resulted in loss of pluripotency [30].
The very ends of eukaryotic linear chromosomes are additionally protected by
the telomeric overhangs [19]. As telomeres, they are shorter in differentiated
progeny of ESCs [31]. The Tert overexpression in mouse ESCs not only increased
their telomerase activity but also extended the length of overhangs,
simultaneously elevating ESC proliferative capacity and resistance to apoptosis [31].
Epigenetic factors, such as histone
modifications and DNA methylation, play an important role in establishing and
maintaining pluripotency of ESCs [32,33]. Not surprisingly, the telomere
homeostasis is also under epigenetic control [34,35]. Moreover, this control
could be species-specific [36]. As typical for pluripotent stem cells, ESCs
have more relaxed chromatin conformation, including telomeric regions [27,37,38].
Accordingly, ESCs have a higher number of open chromatin markers, acetylated
and methylated lysine 27 of histone 3, in combination with trimethylated
histone 3 lysine in non-expressing genes [39]. Modification of the di/tri
methylated lysine ratio at regulatory regions of ESCs was sufficient for
acquisition or repression of cell lineage transcriptional program and
phenotypes [39]. Methylation of cytosine (5mC) is another powerful tool of
epigenetics. Oxidation of 5mC by the Tet protein family results in formation of
oxidized derivatives of 5mC. They are selectively recognized and excised by
thymine DNA glycosylase, thus leading to DNA demethylation. Tet knockout ESCs
exhibit elongated telomeres and elevated telomere-sister chromatid exchange,
indicating the direct impact of DNA demethylation on telomere homeostasis [40].
In cell cultures, ESCs exist as a mixture of
metastable cells sporadically entering into the 2-cell embryo-like state. The
genes Zscan4, Tcstv1 and Tcstv3 were shown to be involved in the formation of
this state; they were also responsible for telomere maintenance and genomic
stability [41,42]. Ectopic overexpression Tcstv1 or Tcstv3 genes resulted in
telomere elongation, whereas their knockdown shortened telomeres of ESC [42].
Telomerase in
cellular senescence, aging and rejuvenation
Aging is often referred as to a progressive
decline in tissue homeostasis and repair caused by malfunction of somatic stem
cells, accompanied by accumulation of senescent cells [17,43,44]. However,
there is a growing consensus that cellular senescence and aging are reversible
[45-48]. Somatic cells can be rejuvenated back to the ESC-like state by various
procedures of induced pluripotency, nuclear transferring, fusing with ESCs,
tetraploid embryo complementation or exposure of somatic cells to ESC extracts.
The essential point is that the viable pups could be derived from cell clones
rejuvenated by all these procedures [27,41,49,50]. For example, treatment of
mouse fibroblasts with ESC protein extracts was sufficient for reprogramming
the adult fibroblasts into ESC-like cells [41]. Moreover, these cells were
functionally and biologically indistinguishable from ESCs and exhibited
complete developmental potency, giving rise to fetal animals. The ESC
extract-induced alterations in the global gene expression, DNA methylation and
histone modifications were typical for the conversion of somatic cells into pluripotent
stem cells. In another study [12], the mouse ESC-conditioned medium
supplemented to cultured human dermal fibroblasts was shown to suppress
cellular senescence and maintain their proliferative capacity, presumably,
through up-regulation of fibroblast growth factor 2 and down-regulation of
CS-associated p53.
The microarray
analysis showed that the enhanced self-renewal and extended lifespan of cells
were associated with activation of a variety of genes. Among them, telomerase
was suggested as a “survival enzyme” in ESCs and their differentiated progeny [31].
Cellular rejuvenation is ubiquitously associated with telomerase activation and
telomere elongation, supporting the idea of “cause-and-effect” relationships
between aging and telomere integrity [51]. Moreover, there is evidence that
telomere size established by ESCs could be deterministic for mammalian
longevity [52,53].
IT IS BETTER TO DIE THAN TO
BE WRONG
This “Samurai
Law of Biology” [54] is especially relevant to ESCs. In contrast to the mostly local
effects of somatic cell failure, DNA damage and mutations in ESCs could have
catastrophic consequences for most tissues and the whole organism and may also
be passed to the germline progenies. This assumes that ESCs should
evolutionarily be rendered superior defense and selection systems. Indeed, ESCs
are characterized by a robust DNA repair and low levels of mutations [55-57].
For example, spontaneous or induced mutation frequency of the reporter genes
was several orders of magnitude lower in mouse ESCs than in the embryo
fibroblasts. Yet, DNA breaks are rather frequent in ESCs, especially during DNA
replication [58]. Homologous recombination is recognized as the main pathway of
DNA double strand breaks (DSBs) repair and Rad51 is a key regulator of this
process [59]. In mouse ESCs, Rad51 showed a 2-fold increase in mRNA and 15-fold
increase in protein expression, compared with the embryo fibroblasts. Moreover,
only a small portion of Rad51 protein was recruited to repair DSBs or stalled
replication forks in normal conditions, thus indicating substantial reserves of
Rad51-dependent DNA repair in stressful conditions [60].
Further
supporting superior protection of ESC vs. differentiated cells are lower rates
of free radical generation in combination with a higher antioxidant defense
[61]. Measurements of 8-OH-G (8-hydroxyguanine), a well-known marker of
oxidative stress damage in DNA, showed that ESCs cultured with 300 μM hydrogen
peroxide had lower levels of 8-OH-G than more differentiated cells. The better
protection of ESC DNA against free radicals was further supported by an
enhanced expression of 8-OH-G repair-associated genes [62]. It appears that
ESCs and their genome are more resistant to oxidative stress. Degradation of
misfolded, aggregated or otherwise damaged proteins via autophagy or
proteasomes was also superior in ESCs, thus underpinning their generally
ameliorated intracellular environment [63,64].
Apart from a
robust DNA repair and a low mutational level, hypersensitivity of ESCs to
apoptosis is another important tool to protect their genome integrity. ESCs
with unrepaired DNA damage readily undergo apoptosis or differentiation, thus
removing the damaged cells from the pluripotent pool [65,66]. In fact, ESCs and
their differentiated progeny adhere to different stress response strategies [67].
For example, sub lethal heating activated apoptosis in human ESCs while induced
premature senescence in the ESC-derived fibroblast-like cells [68]. Another
example includes hypersensitivity of ESCs to camptothecin, a topoisomerase I
inhibitor which induces DNA DSBs and an intensive p53-mediated apoptosis in
human ESCs, but to a much lesser degree in differentiated ESCs [69]. The
importance of genome integrity in ESCs is further exemplified by mice deficient
in Cdk12 (cyclin-dependent kinase 12), a multifunctional protein involved in
maintaining the genomic stability and pluripotency of ESCs [58]. The Cdk12−/−
embryos displayed a reduced expression of DNA damage response genes and
insufficient DNA repair, with subsequent activation of apoptosis. This resulted
in abrogated accumulation of the inner cell mass in blastocysts and lethality
of the embryos shortly after the implantation [58]. Of note, an increased DNA
repair and sensitivity to apoptosis have been observed in several models of
lifespan extension [44].
ESCs RESIDE
IN HYPOXIC/HYPERCAPNIC MICROENVIRONMENT AND RELY ON GLYCOLYSIS
Increased
sensitivity to apoptosis and completely de-differentiated status of ESCs
apparently require a low metabolic rate associated with less production of ROS.
This could be supported by hypoxic/hypercapnic microenvironment which is
optimal not only for ESCs but for other stem cells as well [70-72]. ESCs are
usually obtained from the inner cell mass of pre-implantation embryos
(blastocysts). While moving down the oviduct towards the uterus, embryos
continue dividing and reach a considerable size at the pre-implantation
blastocysts. At this stage, there are usually several hundreds of the inner
mass cells and comparable number of cells of the outer layer of the blastocyst-trophoblast
[73]. Lack of vascularization or other mechanisms of O2/CO2
active transport, aggravated by the assembly of substantial number of ESCs,
means that ESC environment in the blastocyst cavity (blastocoele) is
essentially hypoxic/hypercapnic. We hypothesized that the severe
hypoxia/hypercapnia in blastocysts is required for suppression of ESC
differentiation, thus allowing a highly efficient DNA repair — a crucial event
before ESCs start to differentiate. Besides, this temporary suppression allows
synchronizing a consequent differentiation of ESCs.
Such
hypoxic/hypercapnic microenvironment will decrease the rate of oxidative
phosphorylation (and accordingly, ROS generation) and activate glycolysis, in
part due to the hypoxia inducible factor 1 alpha (Hif1alpha) which
concomitantly promotes telomerase expression and enhance self-renewal of stem
cells [74]. Anaerobic metabolism could also be necessary to supply substrates
for the anabolic processes, which is typical for intensively dividing cells
(Warburg effect) [75,76]. In fact, activated glycolysis and associated higher
concentrations of pyruvate and lactate are metabolic hallmarks of apparently
all actively dividing cells, ESCs included [77-79]. In the in vitro
cultured early mouse embryos, glucose consumption was undetectable until the
blastocyst stage but became the main source of energy generation in the later
stages (embryo’s day 6.5 and 7.5), in contrast to the opposite dynamics of
pyruvate utilization [80]. Of note, almost the same pattern of metabolic
alterations was observed in various models of induced pluripotency which
usually started by inhibition of oxidative phosphorylation and activation of
glycolysis [81,82]. Remarkably, even at high levels of O2, ESCs
utilized primarily the anaerobic metabolism [83]. This apparently allowed them
to survive hyperoxia by reducing the ROS generation. Another important finding
is that the main transcription factors of pluripotency, Oct4 and Nanog, can
directly induce expression of the key glycolytic enzymes hexokinase 2 and
pyruvate kinase M2, thus delaying differentiation and preserving pluripotency
of ESCs [84]. In turn, the genes involved in the control of glucose uptake
(GLUT3) and metabolism (PKM2) are also involved in regulation of Oct4
expression [85]. It should be emphasized that even though the pluripotent stem
cells rely on glycolysis, mitochondria also play an important role in the
maintenance of pluripotency [79]. In particular, several mitochondrial genes
(e.g. POLG, Gfer, Drp1) were shown to regulate the expression of pluripotent
factors.
CONCLUDING
REMARKS
ESCs belong to
the enigmatic group of immortal, pluripotent cells. Successes in nuclear
reprogramming, induced pluripotency and other related protocols make these
naturally pluripotent cells “gold standard” for comparison, understanding of
the basic mechanisms of pluripotency and for the development of new
biotechnologies. The huge potential of ESC application in anti-aging remains
insufficiently explored, warranting further research in the field.
Pluripotency of
ESCs is supported by complex networks of the growth and transcription factors,
primarily by Oct4, Sox2 and Nanog, which expression is under a strict
epigenetic control. Survival and proper functionality of ESCs and their
differentiated progeny strongly depend on the telomere homeostasis [26], which
apparently has wider assignments than just canonical protection of the
chromosomes ends. Whatever the case, telomeres and telomerase are key
regulators of stem cell proliferation, simultaneously restraining cancer and
delaying aging [86].
ESCs have
superior mechanisms for DNA repair and genome maintenance. Yet, being
potentially immortal in cultures, ESCs are predisposed to apoptosis instead of
trying to repair the damage ― an additional line of protection of the ESC
progeny. Despite the efficient DNA repair, generally well-maintained telomere
homeostasis and sensitivity to apoptosis, long-term manipulations with ESCs
in vitro often lead to genomic and epigenomic abnormalities, with a
subsequent decrease in cell viability or acquiring tumorigenicity [32,87,88].
These aspects of ESC and iPSC biology have not yet been fully addressed and
definitely require more attention.
An important
point is that ESCs live in hypoxic/hypercapnic microenvironment, as apparently
once did the last universal common ancestor (LUCA)
of all animal species in primordial Earth atmospheres. On the one hand, such
microenvironment ensures minimal generation of ROS due to glycolysis-based
metabolism. On the other hand, it promotes conditions for efficient DNA
repair. This is especially true for ESCs of the pre-implanted blastocyst, when
hypoxia/hypercapnia reaches its peak. This short period of ESC life
provides a unique opportunity for the “last-minute” correction of the DNA
damage, before ESCs start to differentiate. The very fact that the life still
exists, and the accumulated damage does not pass on from generation to
generation is, to a great extent, guaranteed by that “last-minute” correction
of ESCs.
ACKNOWLEDGEMENT
This work was
supported in part by the Fund in Memory of Dr. Amir Abramovich. We appreciate
the assistance of Mrs. Anna Knyazer in preparation of the manuscript. We would
like to apologize to those whose work we did not cite because of huge number of
publications in the field.
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