Tissue Engineering: Focus on the Musculoskeletal System - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 201

to promote ADSC proliferation and inhibit apoptosis under hypoxia con-
ditions in vitro. Furthermore, the presence of FGF2 increased VEGF and
HGF mRNA expression under hypoxia conditions, indicating that FGF2
promotes ADSC survival and also up-regulates their angiogenic capability.
When injected into the ischemic hind limb, limb perfusion was increased
to approximately 55% (relative to non-ischemic), while ADSCs without FGF
remained at approximately 35% (non-cell carriers did not increase above
20%). Groups treated with FGF/ADSC also led to significant enhanced limb
salvage (4 out of 10) compared to the control (0 out of 10) (Figure 9.3). This
work demonstrates the promise of using a combination of ADSC and bio-
materials therapy for promoting tissue regeneration.
Induced Pluripotent Stem Cells
For repairing large tissue defects, it is often a challenge to obtain a large
number of cells that can differentiate into the desired cell phenotype without
immunogenicity. The recent discovery of induced pluripotent stem cells (iPS)
will likely provide a solution to this problem by reprogramming the patient's
own differentiated cells back to a pluripotent state. Takahashi and Yamanaka
first proved in 2006 that embryonic-like stem cells could be derived from
adult fibroblasts, which can then be used to generate any type of differenti-
ated cells for repairing tissues [31]. Re-programming was achieved by virally
introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, into adult fibroblasts
under embryonic stem cell culture conditions. When injected subcutane-
ously into a mouse model, tumors formed containing a variety of tissues
from all three germ lines, which confirmed the pluripotency of these cells.
While the iPSCs demonstrated a lot of similarity to ESCs in terms of cell
morphology, proliferation, pluripotency and tumorigenicity, they express a
global gene expression pattern different from that of embryonic stem cells
[32]. In a follow-up study by the same research group, germline transmission
was achieved by using more specific markers for iPS selection, and adult
chimaeras were successfully obtained from iPS cell clones [33]. Within this
study, 20% of the offspring developed tumors attributed to reactivation of
the c-myc transgene. While the work with iPSC is still relatively new, it holds
great promise for wide applications for repairing musculoskeletal tissues,
where large defects are common and iPSCs would offer a source for gen-
erating all the desired cell types, including osteoblasts, chondrocytes, and
endothelial cells. More work needs to be done to control the specific differen-
tiation of iPSCs towards these lineages by defining the right induction cues.
Cell Homing
Localizing the transplanted cells to the disease or defect site in vivo is impor-
tant for successful tissue repair, and biological signals may be used to guide
such homing processes. Upon intravenous injection, hematopoietic stem