A growth factor isolated from human stem
cells shows promising results in a mouse model of multiple sclerosis.
Human
mesenchymal stem cells (hMSCs) have become a popular potential therapy for
numerous autoimmune and neurological disorders. But while these bone
marrow-derived stem cells have been studied in great detail in the dish,
scientists know little about how they modulate the immune system and promote
tissue repair in living organisms.
Now,
one research team has uncovered a molecular mechanism by which hMSCs promote
recovery in a mouse model of multiple sclerosis (MS).
According
to research, published online Sunday (May 20) in Nature Neuroscience, a growth
factor produced by hMSCs fights MS in two ways: blocking a destructive
autoimmune response and repairing neuronal damage. The finding could help
advance ongoing clinical trials testing hMSCs as a therapy for MS.
The
researchers have identified “a unique factor that has surprisingly potent
activity mediating neuron repair,” said Jacques Galipeau, a cell therapy
researcher at Emory University in Atlanta, Georgia, who was not involved in the
research. “The magnitude of the effect on a mouse model of MS is a big deal.”
MS is
an autoimmune disease in which the immune system attacks myelin sheaths that
surround and protect nerve cells. The attack leaves nerves exposed and unable
to send signals to the brain and back, resulting in the loss of motor skills,
coordination, vision, and cognitive abilities. There is no cure for MS, and
most current therapies work to simply suppress the immune system, preventing
further neuronal damage. None have demonstrated an ability to also repair
damaged myelin and promote recovery.
In
2009, Robert Miller and colleagues at Case Western Reserve University in
Cleveland, Ohio, demonstrated that hMSCs dramatically reversed the symptoms of
multiple sclerosis in a mouse model of the disorder. “The animals got better,”
recalled Miller. The team hypothesized that the stem cells suppress the immune response
and promote remyelination.
But
Miller wanted to know exactly what the cells were doing. To find out, his team
isolated the medium on which the hMSCs were grown to determine if the cells or
something they secreted was responsible for the observed recovery. The medium
alone was enough to induce recovery in mice, pointing to the latter.
To find
out exactly which molecule or molecules in the medium were responsible, the
researchers separated the proteins in the fluid based on the molecular weight
and injected each isolate into mice exhibiting symptoms of MS. The mid-weight
solution, of proteins with masses between 50 and 100 kilodaltons (kDa), caused
recovery. “That eliminated a huge number of potential candidates,” said Miller.
The
researchers then narrowed the field again with a literature search for a
molecule that fit their criteria: secreted by hMSCs, 50-100 kDa in size, and
involved in tissue repair. They identified hepatocyte growth factor (HGF), a
cytokine made by mesenchymal cells that has been shown to promote tissue
regeneration and cell survival in numerous experiments. Sure enough, HGF alone
was enough to promote recovery in the MS mouse models, and blocking the
receptor for HGF in those mice blocked recovery. The team also demonstrated
that HGF suppresses immune responses in vivo and accelerates remyelination of
neurons in vitro. Finally, they saw that HGF causes remyelination in rats with
a lesion on their spinal cord.
“I feel
quite confident that HGF suppresses the immune response and also drives myelin
repair,” said Miller. There are likely other hMSCs-produced factors that
contribute to the cells’ beneficial effect, but HGF is certainly critical, he
said. “The data are compelling,” added Galipeau.
There
are currently several clinical trials testing hMSCs in MS patients around the
world, including a phase I trial at the Cleveland Clinic in Ohio that emerged
from the work in Miller’s lab. The new mechanistic information could help
researchers designing those therapies to select cells that produce high levels
of HGF, said Miller, which should promote remyelination and maximize symptom
reversal.
But the
research begs a question: why not simply forgo the cells altogether? That point
is up for debate. Miller argues that stem cells act as vehicles to transport
HGF, and other potential factors, directly to the central nervous system and
maintain production there. But a single protein is a far more practical
therapy—cheaper and easier to produce—than a cell therapy, countered Galipeau.
“The best cell therapy is one done without a cell,” he said. “Identifying these
factors and testing them as single agents is an important short-term
deliverable of stem cell science.”
To find
out more about which cell therapies are in clinical trials, stay tuned for the
July issue of The Scientist, featuring an analysis of the growing cell therapy
industry.
L. Bai et al., “Hepatocyte growth factor mediates
mesenchymal stem cell–induced recovery in multiple sclerosis models,” Nat
Neuro, doi:10.1038/nn.3109, 2012.
Megan
Scudellari
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