Biomedical Engineering Reference
In-Depth Information
infiltration. Furthermore, the MSCs were able to significantly improve muscle
regeneration, compared to saline injected controls, by activating host progenitor
cells as well as by fusing with preexisting fibers [
42
]. In vitro evidence suggests
that MSCs may exert particularly useful effects on macrophage phenotypes.
So-called ''wound healing,'' or alternatively activated macrophages, typically
classified as an M2 phenotype, exert many anti-inflammatory, and pro-wound
healing effects. M2a macrophages, which are activated via IL-4 and IL-10, stim-
ulate myoblast proliferation and protect myotubes from M1 mediated membrane
lysis [
43
]. MSCs have been demonstrated to bias macrophages towards an M2a
phenotype in vitro [
44
]. Therefore, use of MSCs may have the potential to
decrease inflammation in the host and improve muscle regeneration through
multiple mechanisms.
Some may argue that a more myogenic cell source than MSCs is required to
regenerate significant amounts of normal (donor-derived) rather than dystrophic
(host-derived) muscle, which is still susceptible to continued degeneration. Within
skeletal muscle, multiple stem/progenitor cells have been isolated, in addition to
SCs [
3
]. Our group has identified a highly myogenic cell population in murine
muscle, termed muscle-derived stem cells (MDSCs), which exhibit a higher
intramuscular engraftment capacity compared to myoblasts [
45
]. Isolated by a
modified preplate technique, which separates cell populations based on their
adhesion characteristics, MDSCs are slow to adhere and appear to represent a
progenitor population less committed to the myogenic lineage, as they are able to
undergo multi-lineage differentiation and long-term proliferation in vivo [
46
].
When donor cells are transplanted into an inflammatory environment, such as that
found in DMD, free radicals released from activated leukocytes can induce oxi-
dative stress in donor cells. Evidence from murine studies suggests that the rela-
tively high level of MDSC engraftment may be due to a strong resistance to stress-
induced apoptosis resulting from high levels of the cellular antioxidant glutathione
and the enzyme superoxide dismutase [
47
]. MDSCs have also been found to aid in
the repair of normal injured muscle. Using a skeletal muscle contusion injury
model, MDSC transplantation accelerated healing by enhancing angiogenesis [
48
].
In addition to skeletal muscle, murine MDSCs have been found to aid in the repair
of bone and cartilage defects, and improve heart function in murine models of
acute myocardial infarction [
49
-
51
]. Slowly adhering cells isolated from human
muscle have also been found to display similar skeletal and cardiac muscle
regeneration properties [
52
,
53
]. Furthermore, clinical trials of human slowly
adhering cell-based therapies are currently underway for the treatment of urinary
incontinence [
54
]. Additionally, Rouger and colleagues recently reported that
systemic delivery of allogeneic wild type canine slowly adhering muscle-derived
cells to dystrophic dogs significantly improves disease phenotype. Donor cells
were found to not only contribute to muscle regeneration, but they replenished the
SC niche, resulting in long-term dystrophin expression [
55
]. If such results are able
to translate to humans, slowly adhering muscle-derived cells may be able to be
delivered
systemically,
an
option
not
possible
for
myoblasts,
which
cannot
extravasate from circulation.
