The Role of MicroRNAs in Natural Tissue Development and Application in Regenerative Medicine - RNA Interference from Biology to Therapeutics - page 65

3.3.5 Cell Survival

One of the major obstacles in any tissue engineering strategy employing trans-
planted cells is to ensure cell survival upon implantation. MicroRNAs play impor-
tant roles in cell survival and modulating miRNA levels may, therefore, be used to
promote cell survival. This is especially important with cells that display very limited
proliferative capacity or post-transplantation survival such as cardiomyocytes. In
one study, overexpression of a cocktail of miR-21, miR-24 and miR-221 from len-
tiviral vectors promoted survival of transduced cardiac progenitor cells both in vitro
under serum-free condition and in vivo after intramuscular injection [ 4 ] . Injection
of cardiac progenitor cells, overexpressing the miRNA cocktail, in ischemic heart
myocardium led to improved function and reduced infarction size compared to
injections of non-transfected cells. The microRNAs used acted partly by repressing
a number of apoptotic genes, notably BIM which is a critical apoptotic activator,
leading to less activated Caspase 3. Similarly, in another study, it was shown that
diabetic cardiomyopathy was partly driven by the progressive loss of PIM1, whose
restoration after gene therapy led to improved heart function [ 71 ] . PIM1 is repressed
by miR-1, and it was found that transfecting cardiomyocytes with an anti-miR
against miR1 led to increased cell survival as revealed by increased anti-apoptotic
gene expression and lowered caspase activity.

3.3.6 Proliferation and Senescence

The adult body contains some 100 trillion cells [ 72 ]; therefore, growing a tissue or
organ of any significant volume requires a large amount of cells. This is typically
achieved by expanding explanted cells in vitro before they are re-implanted into the
patient. Many ill patients, however, cannot wait long periods for a replacement
organ. In order to generate a large number of cells in a short time, there is a need for
increasing cell proliferation during the in vitro culture. Unfortunately, the prolifera-
tion of adult stem cells is limited by senescence. When cells are explanted and
expanded, in vitro adult stem cells will experience successive telomere shortening
and finally stop dividing. Previous efforts to circumvent the senescence barrier in
adult stem cells have focused on the activity of the telomerase gene, which, if trans-
duced into these cells, causes a dramatic increase in proliferation capacity [ 73 ] .
However, recent results indicate that miRNAs also play a role in senescence, for
example, microRNA-486-5p, which represses SIRT1, a major regulator of longev-
ity and metabolic disorders. Blocking the function of this miRNA with anti-miR-
NAs was shown to inhibit senescence and promote cell proliferation [ 74 ] .