The Role of MicroRNAs in Natural Tissue Development and Application in Regenerative Medicine - RNA Interference from Biology to Therapeutics - page 64

[ 64 ], while antagonists against miR-16 and miR-424 induce secretion of VEGF
[ 65 ] .

3.3.3 MicroRNAs and Induced Pluripotent Stem Cell Generation

Another potential use of microRNAs in regenerative medicine is to promote the
generation of IPSC from somatic adult cells, a use that is related to the major role of
miRNA in embryonic stem cells. The generation of IPSC cells is usually performed
using gene therapy with a vector encoding the pluripotency genes OCT3/4, SOX2
and KLF4. However, a major obstacle is the P53 tumour suppressor protein, which
partly through P21 counteracts IPSC formation [ 66 ]. These proteins act, in part, by
increasing the levels of certain miRNAs, for example miR-34 [ 67 ] , which in turn
silence the expression of pluripotency genes such as NANOG, SOX2 and MYCN.
Hence, the expression of these microRNAs represents a barrier for the generation of
enough IPSCs for practical purposes. Such microRNAs would potentially be ideal
targets for anti-miRNAs for enhancing IPSC formation. Other miRNAs, for exam-
ple miR-93 and miR-106b [ 68 ], are induced during early dedifferentiation in which
they silence P21 leading to further de-specialisation. Increasing the amount of these
miRNAs in fibroblasts by introducing miRNA mimics can potentially be used to
promote IPSC formation. The increasing possibilities for regulating key genes
involved in IPSC formation and maintenance suggests that it may be possible to
drive dedifferentiation with miRNA and anti-miRNA alone, thereby avoiding prob-
lematic viral vectors and the overexpression of oncogenes associated with the cur-
rent methods [ 69 ] .

3.3.4 Immune Modulation

The immune system is an important component in regenerative medicine; it is a
primary target for strategies that seek to reduce localised inflammation and subse-
quent tissue destruction prior to regeneration. MicroRNA-155, for example, is
upregulated in rheumatoid arthritis where it down regulates SHIP1, an inhibitor of
in fl ammation [ 70 ]. In contrast, miRNA-146a alleviates rheumatoid arthritis by
inhibiting the differentiation of monocytes and macrophages into multi-nucleated
osteoclasts, which are responsible for joint destruction [ 3 ] . Incidentally miR-146a
also seems to be involved in promoting de novo osteogenesis of cells [ 37 ] , and it
may, thus, play a dual role both reducing tissue inflammation and increasing regen-
eration. MicroRNA-mediated modulation of immune responses, therefore, presents
a strategy to arrest further tissue degeneration before regeneration is induced.