Journal of Cell and Molecular Biology - ResearchGate

chemotherapy which has many different
mechanisms of action within the cell preventing
proliferation. However, p53, being in high
concentration in cancers, may have the ability to
form TNTs. The questions that need to be asked
are: 1) Do cancers cells with high concentrations of
p53 also produce TNTs? 2) Does the treatment of
chemotherapy drugs increase TNT formation? 3)
Do resistant cancers have the ability to produce
TNTs when treated with chemotherapy drugs?
Virus and prion exchange
TNTs also provide a way for pathogens to migrate
from one cell to another and proliferate. HIV was
discovered to use TNTs to migrate from one cell to
another, evading the extracellular environment in
human monocyte-derived macrophages (MDM)
and avoiding the host’s immune cells (Kadiu and
Gendelman, 2011; Eugenin et al., 2009). It was
found that HIV depended upon entering a MDM
via clathrin-mediated endocytosis. This process
encapsulates the virus and allows it to pass through
F-actin and microtubule derived TNTs to a
neighbouring cell (Kadiu and Gendelman, 2011).
Again with T-cells, HIV was found to use TNTs as
a way of infecting neighbouring cells and also
increase the numbers of TNT formations without
having to spread via the extracellular fluid
(Sowinski et al., 2008). These data demonstrate
how viruses have the ability to use host immune
cells to migrate and proliferate in vitro without
contacting the extracellular fluid. Prions have also
been identified to migrate between cells using
TNTs (Gousset et al., 2009). Prions are misfolded
proteins that are capable of entering a cell and
altering wild-type proteins leading to diseases like
Creutzfeldt-Jakob disease (CJD) and can cause
necrosis (Brundin et al., 2010). It was identified
that TNTs can aid the spreading of prions in
cultured cells from Cath. a-differentiated (CAD)
cell line (Gousset et al., 2009).
The use and passage of mitochondria from
damaged to healthy cells in the brain may be a
cause of spreading neural diseases, e.g. AD and PD.
Three research questions arise in this area, which
are 1) Does a damaged cell have the ability to both
form and pass ROS-induced damaged mtDNA to a
healthy neighbouring cell? 2) Do the damaged
mitochondria have the ability to begin apoptosis in
the neighbouring cell and again signal for TNT
formation? 3) Can this process be reversed using
stem cells as previously described?
The process of viral entry and migration
through TNTs has now been documented and
Tunneling nanotubes 15
accepted. The ability to move from cell to cell
using TNTs without having to exit and migrate
through the extracellular fluid have provided a new
mechanism of infection for viruses and prions. This
process of “hijacking” TNTs will no doubt be of
interest to virology and more so for the spread of
HIV amongst immune cells. We now know that
viruses promote TNT formation in the infected cell
and allow safe passage to a recipient, can the same
process be blocked and prevent these “hijackers”
from migrating between cells using TNTs?
Stem cells and their ability to repair damage
via TNTs
Stem cells are very much at the forefront of medical
sciences and the hope of curing many diseases rests
upon these progenitor cells. It is surprising, though,
to discover their additional abilities and possible
mechanisms of aiding cells in distress in vitro. It
was discovered that endothelial progenitor cells
(EPC) – a precursor cell to endothelial cells – could
couple with both types of TNT sizes from HUVEC
(Yasuda et al., 2011). It was observed that EPC cocultured
with stressed HUVEC could produce
TNTs and traffic cellular components both ways,
but mainly observed to pass from EPC to HUVEC
(Yasuda et al., 2011). This promoted HUVEC to
recover from stress and to proliferate. Additionally,
mesenchymal stem cells (MSC) were also found to
traffic cellular components via TNTs to damaged
cardiomyoblasts and promote recovery (Cselenyak
et al., 2010). From the research it seems that stem
cells have the ability to repair cells which have
sustained stress. This process of repair rather than
salvaging (as found in non-stem cells in previous
sections of this review) may demonstrate how stem
cells can rescue damaged cells.
Discussion
With the discovery of TNTs and the subsequent
abilities they have in trafficking the molecules,
disease-spreading prions and viruses, it is clear that
these TNTs have a valid place in cellular biology. It
can be agreed that TNTs do provide a function in
cellular communication. There is still a mystery to
TNT-genesis in that it is not fully understood what
mechanisms are in place that signal aid via TNTs.
We do know that stress is a key factor and that
repair/apoptosis mechanisms are in place prior to
TNT development. With further research TNTgenesis
and key communication signals for
coupling may become better understood.
This review paper ventured into diseases
associated with intracellular molecules and viruses