Therapeutic Applications:

Overview: Mesenchymal stem cells (MSCs) are
multipotent stem cells that can differentiate into a variety
of cell types, including osteoblasts, chondrocytes,
myocytes, adipocytes, beta-pancreatic islets cells, and
potentially, neuronal cells.

MSCs are of intense therapeutic interest because they
represent a population of cells with the potential treat a
wide range of acute and degenerative diseases. MSCs are
advantageous over other stem cells types for several
reasons. First, they avoid the ethical issues that surround
embryonic stem cell research. Second, repeated studies
have found that human MSCs are immuno-privileged, and
therefore, represent an advantageous cell type for
allogenic transplantation, reducing the risks of rejection
and complications of transplantation. Recently, there have
also been significant advances in the use of autologous
mesenchymal stem cells to regenerate human tissues,
including cartilage and meniscus, tendons, and bone
fractures.  
Human bone marrow-derived
mesenchymal stem cells (MSCs) are
an attractive target for ex vivo gene
therapy, since they have a high
proliferation capacity and maintainin
vitrothe ability to differentiate into a
variety of mesenchymal tissues such
as bone, cartilage, fat and muscle.

The fact that MSCs can be differentiated into several different cell types in
vitro, their relative ease of expansion in culture, and their immunologic
characteristics clearly make MSCs and MSC-like cells a promising source of
stem cells for tissue repair and gene therapy. However, compared with in vitro
characterization, there is less information on the in vivo behavior of MSCs. The
studies that have been performed can be split into observations following
site-directed or systemic administration of cells.

Site-directed delivery of MSCs has shown their engraftment in several tissues,
particularly after injury. Several groups have used bone marrow cells to repair
infarcted myocardium. Another group injected isolated murine MSCs directly
into healthy adult myocardium and noted neoangiogenesis near the injection
site within 1 week after transplantation. Donor cells could be identified within
these vessels, and it was shown that transplanted cells had differentiated into
cardiomyocytes, endothelial cells, and pericytes or smooth muscle cells,
demonstrating that cultured MSCs have the ability to engraft into healthy as
well as injured tissue and can differentiate into several cell types in vivo.

Hofstetter and colleagues injected rat MSCs into the spinal cords of rats
rendered paraplegic 1 week after injury. They found that MSCs formed bundles
bridging the epicenter of the injury and guided regeneration through the spinal
cord lesion, thus promoting recovery. This implies that the beneficial effect of
MSCs in sites of injury may not necessarily involve their differentiation into the
regenerating tissue type but rather the local production of growth or other
factors or physical attributes such as forming guiding strands in the injured
spinal cord.

Some reports showed that when MSCs are transplanted into fetal or neonatal
animals, they engraft and contribute to many different tissues. Liechty and
colleagues transplanted hMSCs into fetal sheep early in gestation before and
after the expected development of immune competence. In this xenogenic
system, hMSCs engrafted and persisted in multiple tissues for as long as 13
months after transplantation. Transplanted cells underwent site-specific
differentiation into chondrocytes, adipocytes, myocytes and cardiomyocytes,
bone marrow stromal cells, and thymic stroma. Even after development of
immunocompetence, cells were present in liver, bone marrow, spleen, thymus,
adipose tissue, lung, articular cartilage, perivascular areas of the central
nervous system, and cardiac and skeletal muscle, indicative of migration and
engraftment in multiple tissues throughout the body without provoking an
immune response. Another group injected murine MSCs into the lateral
ventricle in the brains of 3-day-old mice and examined the brains 12 days
later. They found that MSCs migrated throughout the forebrain and cerebellum,
suggesting that MSCs mimic the behavior of neural progenitor cells in this
setting. Some MSCs differentiated into astrocytes, and others may have
differentiated into neurons, as indicated by the expression of neurofilaments. It
is likely that a major contributing factor to the behavior of the MSCs in these
two studies is their exposure to tissues and organs still undergoing extensive
development. The signals they respond to in the fetus or neonate will be very
different from those in the adult animal, and hence MSCs may be capable of
differentiating into more cell types in the embryo than in the adult.

Systemic delivery of MSCs has been reported by several groups. Barbash and
colleagues investigated whether cultured MSCs could be successfully delivered
to the infarcted myocardium with a view to repair. They delivered cultured rat
MSCs into the left ventricular cavity of rats 2, 10, and 14 days after induced
myocardial infarction (MI) and compared with sham-MI rats. MSC infusion into
MI rats resulted in significantly higher uptake in the heart than in sham-MI rats;
however, less than 1% of the infused cells resided in the infarcted heart 4
hours after infusion. Early infusion (2 days compared with 14 after MI) also
resulted in significantly higher uptake in the heart. MSCs were preferentially
attracted to, and retained in, the ischemic tissue but not in the remote or intact
myocardium. This suggests that injured tissue might express specific receptors
or ligands to facilitate trafficking, adhesion, and infiltration of MSCs to the site
of injury, but these may be downregulated a fairly short time after injury
occurs. Barbash and colleagues also infused rat MSCs to their MI rats by the
intravenous (IV) route but found the majority of cells in the lungs, with a small
amount engrafting in the heart, liver, and spleen. Some MSCs had still homed
to the site of injury in the heart, but much fewer than after delivery into the
ventricle. Entrapment of donor cells in the lung occurs in other studies where
cultured MSCs are delivered intravenously. This is most likely explained
because expanded MSCs are relatively large and activated and express
adhesion molecules. However, Gao and colleagues found that treatment with
the vasodilator sodium nitroprusside decreased the number of cells entrapped.

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