Although MSC-based tissue engineering strategies have
shown tremendous promise for the regeneration of bone
mass defects, the efficient induction of osteogenesis in
these cells remains a significant roadblock to the
effective implementation of cell-based therapies.
When grown in culture, MSCs remain multipotent,
requiring specific exogenous signals to induce
osteogenic differentiation.
For MSCs used in transplantations, osteoinduction
is generally accomplished by local signals provided by
the host’s own tissues, though this remains difficult to
control and relatively inefficient.
For this reason, osteoinductive signals have been
included in material scaffolds that are used to deliver
MSCs to defect sites, providing additional stimuli for
directing tissue regeneration.
Alternatively, others have genetically engineered
MSCs to overexpress osteoinductive signals such as the
Bone Morphogenesis Protein-2 (BMP-2) growth factor or
the
Core Binding Factor Alpha 1A (CBFA1)
transcription factor (also known as Runx2).
While each of these techniques has shown promise,
the recent discovery of microRNAs (miRNAs) and their
ability to control global gene expression patterns has
offered a potential strategy for directing stem cell
differentiation down specific developmental lineages and
dramatically improving MSC-based techniques for bone
regeneration.
miRNAs are short, non-coding RNA molecules that act to
inhibit the expression of target mRNAs and serve
important regulatory roles in developmental processes.
When expressed, these small RNAs are processed
and incorporated into larger riboprotein complexes that
can target multiple messenger RNAs (mRNAs), shortening
the half-lives of the mRNAs and/or preventing their
translation into functional proteins.
Targeting of these riboprotein complexes to
specific mRNAs is accomplished by sequence-dependent
interactions between the miRNA and the 3’untranslated
regions of the mRNAs, allowing miRNAs to inhibit the
expression of multiple genes containing the same binding
motif.
Often, the genes that are targeted by each miRNA
function in similar metabolic pathways, allowing miRNAs
to coordinately regulate global gene expression patterns
and control cell fates.
As the field of miRNAs has emerged, it became evident
that miRNA expression profiles are celltype-specific and
that miRNAs likely play a significant role in
controlling cellular differentiation.
Because miRNAs can target a wide range of
seemingly unrelated mRNAs, they possess a unique ability
to regulate global gene expression patterns that
ultimately determine cell function.
Moreover, recent comparisons between stem cells
and cells that are terminally differentiated indicate
that miRNA expression profiles become more and more
complex as cells commit to different cell lineages,
leading us to hypothesize that the controlled
manipulation of miRNA activity in hMSCs could promote
osteogenesis and enhance tissue engineering strategies
that involve the use of stem cells for regenerating
bone.
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