Biology Reference
In-Depth Information
The maintenance of the stem cells in their quiescent multipotent state as well as the
coordinated exit from this state upon damage is controlled by microRNAs such as
miR-335 [
32
]. The subsequent differentiation pathway taken is also controlled
tightly by microRNAs. Two well-studied differentiation pathways are osteoblastic
and adipocytic specialisations. Many miRNAs have been shown to be involved in
these processes (summarised in Table
3.1
).
Of the osteogenesis regulating miRNAs, miR-138 seems to regulate a pathway
involving focal adhesion kinase and ERK 1/2 [
5
]. In undifferentiated MSCs, miR-
138 suppresses the expression of the late osteogenic transcription factor OSX,
whereas miR-138 is downregulated, leading to the expression of OSX in connection
with osteogenesis. MicroRNA-20a was recently [
33
] found to be upregulated dur-
ing osteogenesis, resulting in downregulation of adipocyte marker PPARg and of the
osteoblast antagonists BAMBI and CRIM1. These are negative regulators of BMP
signalling. Hence, BMP and the early osteogenic transcription factor RUNX2 were
upregulated in the presence of miR-20a compatible with the observation that this
miRNA induces osteogenesis in human MSC. Co-repressing of PPARg , BAMBI
and CRIM leads to activation of the BMPs/RUNX2 signalling pathway. MicroRNA-
148b, miR-27a and miR-489 may also be involved in osteogenesis [
36
] . MicroRNA-
27a and miR-489 are downregulated during osteogenesis with grancalcin as a
potential target, whereas miR-148b is upregulated.
Numerous miRNAs have also been reported as control factors for adipogenesis
from human MSC. Both miR-371 and miR-369-5p reduce proliferation [
52
] . MiR-
369-5p, however, blocks adipogenesis, whereas miR-371 increases differentiation.
A putative target of miR-371 is FABP4. MicroRNA-221, miR-222 and miR-155
seem to act anti-adipogenic similar to miR-369-5p [
51
]. The levels of these three
miRNAs decrease during differentiation, and overexpression negatively affects adi-
pogenesis. A putative target for miR-221 and miR-222 is cyclin-dependent inhibitor
CDKN1B and for miR-369-5p it is adiponectin [fatty-acid-binding protein (FABP4)].
For two other miRNAs, miR-155 and miR-371, a target has not been identified yet.
3.3.2
Vascularisation
Almost regardless of what tissue is to be generated, there is a need for implant vas-
cularising due to oxygen diffusion limits of 100-200 mm in dense tissue [
60
] . While
adjacent blood vessels can neo-vascularise biodegradable implants [
61
] , the elapsed
time before sufficient vascularisation has occurred may lead to necrotic zones at the
cores of larger implants. Vascular tissue is composed of endothelial cells surrounded
by smooth muscle cells (except in the case of capillaries). In tissue engineering the
generation of these two cell types has traditionally been promoted using vascular
endothelial growth factor (VEGF) [
62
] and transforming growth factor beta (TGF-b )
[
63
], respectively. However, microRNAs can also be applied to promote smooth
muscle and endothelial cell differentiation. Transfecting fibroblasts with miR-143
and miR-145, for example, enhance their differentiation into smooth muscle cells
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