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
Mesenchymal Stem Cells - Interest Group
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.