Extremely – low frequency pulsed electromagnetic
fields (ELF-MF) of 50 HZ, 0.8mTesla (rms), are able to
orchestrate stem cell commitment towards one of the most
complex embryogenetic outcomes, inducing cardiogenesis in
embryonic stem cells [72]. ELF-MF are also able to modulate
a cardiogenic program throughout the adulthood, as shown
by the ability to increase the expression of genes needed for
cardiogenesis and the maintenance of a myocardial phenotype
in adult ventricular cardiomyocytes [73].
We have recently shown that asymmetrically conveyed
electromagnetic fields (ACEF) of 2.4 GHz optimize the
expression of pluripotency in mouse ES cells, inducing
myocardial, neuronal and skeletal muscle differentiation
[74]. Similar results are obtained upon exposure to ACEF of
ADhMSCs [75]. This effect is the result of a fine modulation
(initial increase and subsequent transcriptional inhibition) of
the expression of stemness related genes [75]. Exposure to
ACEF was able to induce a biphasic effect, i.e. overexpression
followed by transcriptional inhibition of Sox2, Nanog, Oct3/4,
Klf4 and c-myc in human skin fibroblasts, affording for the
first time a direct high-yield reprogramming of adult nonstem
somatic cells into myocardial, neural and skeletal muscle
cells (about 15-20% for each phenotypic commitment) [76].
For the first time, through the exposure to ACEF we were
able to reverse the process of stem cell senescence in human
adult stem cells (ADhMSCs) subjected to prolonged (30 to 90
days) in vitro expansion [77, 78]. This effect resulted from and
was associated with (i) the activation of a telomerase dependent
pathway, linked to the re-expression of TERT, the gene coding
for the catalytic core of telomerase with subsequent increase
in telomere length [77], (ii) the induction of a telomerase
independent pathway associated with the activation of Bmi-1
and the transient increase in the expression of pluripotency
genes, such as Nanog, Sox2 and Oct4 [77], and (iii) the
resumption of multilineage differentiation potential, as shown
by recovery of high throughput of differentiation along
vasculogenic, osteogenic, and adipogenic fates [78].
On the whole, these findings suggest that electromagnetic
fields may have a role not only in the specification but also
in the persistence of a complex cellular identity. The ability
of electromagnetic fields to drive efficient cardiogenesis
in both embryonic and adult stem cells and to reprogram
even human skin fibroblasts into myocardial-like cells poses
intriguing trans-disciplinary musing. In fact, the heart has the
lowest risk for primary malignant transformation, which may
very rarely develop in the form of cardiac sarcomas [79-81].
Cardiogenesis is the first morphogenetic event in different
animal species, including humans. The risk for tumorigenesis
throughout embryo development is also very rare [5-7]. The
canonical view speculating that primary cardiac malignant
tumors are so rare since cardiac cells divide very rarely
appears to be too simplistic. An alternative although nonmutually
exclusive hypothesis may consider the heart as a
tumor suppressor organ, capable of secreting a large network
of growth regulatory and differentiating peptides that may
potentially limit the onset and progression of a local cancer.
In this regard, the attainment of cardiogenesis in the presence
of either chemical agents or physical stimulation encompasses
the transcription and protein expression of endorphin peptides
[33]. These molecules, besides their role in cardiogenesis [55-57], have long been shown to act as negative regulators for
the development and spreading of different types of cancer
[82-87].
In isolated (stem) cell nuclei endorphin peptides have
been shown to bind and activate nuclear receptors and
signaling leading to the transcription of their own coding
gene (self-sustaining loop), as well as the transcription of
the cardiogenic genes GATA4 and Nkx-2.5 [88, 56]. These
findings suggest that a consistent part of the action of these
growth factors on stem cell dynamics may have occurred
intracellularly (intracrine action) [89, 90]. Cell plasma
membrane has long been considered an insuperable barrier for
hydrosoluble peptides. The discovery that regulatory peptides
and transcription factors can be exchanged among cells being
packaged inside exosomes, acting in an intracrine fashion,
discloses novel paradigms in cell-to-cell communication and
adds further relevance for intracrine regulation of cell biology
[90, 91]. We cannot exclude that cardiogenesis, within its
morphogenetic role, may act as a paracrine/intracrine process
that contributes to make the developing embryo remarkably
refractory to cancerogenic risks. Whether exposure of human
cancer stem cells to electromagnetic fields may resume the
ability to differentiate along a cardiogenic lineage and other
differentiation patterns remain to be elucidated. Addressing
this issue will require thorough investigation in vitro and in
vivo in different animal models for cancerogenesis.
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