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can be blocked by anti-miRNAs (also known as antagomirs) [ 19 ] or miRNA decoys
(also known as sponges) [ 20 ]. Synthetic pre-miRNAs are usually hairpin structures
that are processed like the endogenous pre-miRNAs in the cytoplasm, and their
delivery leads to elevated levels of RISC-associated mature miRNA. Anti-miRNAs
are typically modified oligonucleotides with a sequence that is complementary to
the guide strand of a mature miRNA, which they bind tightly thereby blocking their
subsequent RISC guidance. MicroRNA decoys are transcribed in the nucleus from
an exogenously introduced DNA vector and are regular RNA transcripts that con-
tain multiple targets sites for a particular miRNA species, effectively depleting the
miRNA from its real target. Modulation of miRNA levels can be prolonged and
even persistent if the miRNA or decoy-miRNA is expressed in the nucleus from an
exogenously introduced vector [ 21 ]. Prolonged expression is typically driven by
plasmids or non-integrating viruses such as adenoviral vectors, whereas persistent
miRNA modulation can be accomplished using integrating retroviral vectors.
3.3
Applications of miRNA in Tissue Regeneration
Regenerative medicine is currently employing a large variety of drugs to promote
tissue repair and stem cell differentiation. Examples include vitamins, hormones,
synthetic low molecular weight drugs as well as larger biologically derived pep-
tides, proteins, viruses, plasmids and various RNA species. If we take osteogenic (or
bone) regeneration as an example, beta glycerol phosphate, the synthetic steroid
dexamethasone, vitamins D and C, growth factors such as the bone morphogenic
proteins (BMPs) in both native and plasmid-expressed forms as well as siRNAs
have been applied to promote osteogenesis [ 22- 25 ]. Such drugs are applied by
direct injection or ex vivo to guide bone cells to produce more bone or to promote
stem cell differentiation into bone. What additional benefits can miRNA bring to
regenerative medicine, and are there advantages compared to traditional drugs?
MicroRNAs often exert natural developmental functions by modulating the lev-
els of several mRNAs working in parallel, thereby causing more dramatic effects
than changing the level of a single gene or protein. But perhaps the most unique
feature of an RNAi-based medicine is the unparalleled flexibility it offers. Once a
delivery system for miRNA modulators has been devised that works with the implant
and cells of interest, that system can be used to deliver a modulator of any miRNA
and, thereby, control numerous cellular functions such as cell survival or differentia-
tion into different cell types. One could, for example, use different miRNAs with the
same delivery system to stimulate the formation of different cell types from stem
cells. Alternatively, one could promote cell survival with one miRNA and differen-
tiation with another. Tissue development and regeneration is a highly complex pro-
cess involving numerous miRNAs, and a complete understanding is still lacking.
However, in the following sections, we will provide examples of various cellular
processes that are regulated by specific miRNAs and exemplify how they can be
used for regenerative purposes.
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