Biomedical Engineering Reference
In-Depth Information
Effectively harnessing the multipotent and self-renewal properties of stem cells
is crucial for their use in the regeneration and healing of tissue-engineered organs.
MSCs have the ability to differentiate into a variety of cells that constitute tracheal
tissue including chondrocytes [
81
], endothelial cells (ECs) [
57
], fibroblasts [
23
],
and EPCs [
82
]. MSCs contribute to the repair of diseased and damaged lung
tissues [
76
] also by their ability to suppress inflammation [
75
].
MSCs migrate to, and localise at, sites of inflammation due to their chemotactic
and proliferative response to pro-inflammatory cytokines such as TNF-a [
60
].
They can down-regulate the secretion of pro-inflammatory cytokines by macro-
phages [
1
], and are associated with the upregulation of anti-inflammatory cyto-
kines including IL-10, which may be secreted by MSCs directly [
17
]orby
macrophages that have been converted into their alternatively-activated form by
MSCs [
93
]. MSCs are recruited from the bone marrow of the host to the lung
tissue to bring about healing, and this is associated with increased levels of
granulocyte macrophage colony-stimulating factor (GM-CSF) and granulocyte
stimulating factor (G-CSF) [
68
]. The mechanisms by which MSCs are released
from the bone marrow and migrate through the body to damaged tissues are similar
to those of immune cells such as leukocytes [
89
]. GM-CSF and G-CSF are known
to be produced endogenously by macrophages, ECs and fibroblasts in wounds. The
exogenous application of these substances to the tissue-engineered trachea [
6
] can
further boost the recruitment of MSCs and aid the regeneration process. However
the numbers of endogenous MSCs arriving at the implant site may be small so
intra-operative application of exogenous MSCs is performed to aid regeneration.
In addition to applying stem cells to regenerate the trachea, a 'cocktail' of
growth factors and hormones are added to boost the healing process [
6
]. These
include the hormone erythropoietin (EPO) which is used to increase the numbers
of MSCs and stimulate angiogenesis [
39
]. EPO also dampens down inflammation
by down-regulating the production of cytokines by pro-inflammatory cells. EPO
prevents cell apoptosis [
78
], stimulates the secretion of angiogenic factors by
MSCs, and mobilizes endothelial progenitor cells from the bone marrow [
32
].
To enhance proliferation and differentiation of MSCs into chondrocytes, the
growth factor TGF-b (TGF-b1
;
2
;
3) [
12
] is applied to the tissue-engineered tra-
chea intraoperatively [
6
]. Chondrocytic differentiation of MSCs can be caused by
factors produced by chondrocytes themselves [
34
], which includes TGF-b1 pro-
duced by MSCs and MSC-derived chondrocytes [
94
]. Certain ECM components
have been shown to induce differentiation of MSCs into chondrocytes [
22
]
including hyaluronic acid and autologous synovial fluid [
29
]. A variety of other
intrinsic factors, such as hypoxic stress caused by the initial absence of a vascu-
lature, can also influence commitment.
Complete regeneration of the trachea requires the ingrowth of blood vessels to
supply nutrients and remove waste products. This process, angiogenesis, involves
a complex sequence of events commencing with the secretion of growth factors
such as VEGF and bFGF that induces chemotaxis of ECs and their assembly into
hollow tubes that join to form an interconnected network of vessels [
2
]. In a
normal healthy trachea blood vessels cover the outer surface and connect the
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