Biomedical Engineering Reference
In-Depth Information
Our own studies with AD-MSCs have demonstrated an age-dependent decline in cell
proliferation as well as a decreased expression of pluripotent associated genes (NANOG,
OCT, and LIN28A). These changes are related to an impaired osteogenic differentiation due
to age [95]. In the same line of evidence, we have been able to show that the reduction of the
global methylation in AD-MSCs improves hepatic differentiation. These findings clearly
demonstrate that the epigenetic modification of ASCs improves the differentiation potential
of MSCs. The most interesting finding was that 5-azacytidine (AZA), a well-known DNA
methyltransferase inhibitor, and BIX01294 (BIX), a histone deacetylase inhibitor, are
equally able to improve the differentiation capacity of AD-MSCs towards hepatocyte-like
cells. The authors have even been able to demonstrate the partial rejuvenation of old
AD-MSCs [24].
The epigenetic modification of the genome apparently plays a significant role as a
regulatory pathway in the control of stem-cell aging. These changes are mainly identified
in DNA methylation and chromatin remodeling [96]. Increased global DNA methylation
has been observed in many aged adult tissue and cell types [86]. Recently, it has been
reported that ten-eleven translocation (TET) proteins mediate the conversion of 5-methyl
cytosine (5mC) to 5-hydroymethyl-cytosine (5hmC), which plays a crucial role in DNA
demethylation in embryonic stem cells [97]. Our own group has been able to demonstrate
for the first time that TET proteins also mediate the conversion of 5mC to 5hmC in
AD-MSCs. In donors with old AD-MSCs, we have observed a lower level of expression of
5hmC, together with a higher level of expression of 5mC. This finding suggests a DNA
hypermethylation pattern in aged AD-MSCs [98]. Furthermore, it has been shown that the
growth and the osteogenic differentiation potential of old adult AD-MSCs have been
improved by the pretreatment with small molecules AZA and BIX. A gene expression anal-
ysis of pluripotent markers (NANOG, OCT-4, lIN28A, SOX2) has revealed age-dependent
changes in AD-MSCs which suggest that an increase in age leads to a reduction of DNA
demethylation activity. Moreover, it has been demonstrated that TET2 and TET3 gene
expressions are increased by treatment with AZA and BIX. This suggests that TET2 and
TET3 might be involved in the conversion of 5mC to 5hmC in AD-MSCs [99]. However,
the specific role of TET2 and TET3 in the process of aging will require further
investigation.
In summary, these data suggest that a reduction of the DNA demethylation activity in
AD-MSCs correlates with an increased donor age. Furthermore, the treatment of AD-MSCs
with small molecules (AZA, BIX) is able to restore the growth and the differentiation potential
of these cells.
Stem Cells in Regenerative Medicine and
in vitro
Application
Regenerative medicine is a multidisciplinary field of research. It includes the use of bioma-
terials, growth factors, and stem cells for repairing, replacing, or regenerating damaged tis-
sues and organs.
Due to their self-renewal and differentiation capacity, stem cells are ideal candidates for
an application in regenerative medicine [62]. However, many questions about the criteria
that should define the application of stem cells in regenerative medicine still have to be
answered.
The first and foremost problem that needs to be solved consists in finding a possibility to
access the millions or even billions of ASCs that can be found in every human body. Second,
it has to be analyzed whether the stem cells can be harvested in an
in vitro
environment
