though, scientists need to give the cells
every possible advantage, nudging them
toward chondrocytic behavior. In the
lab, the cells are typically mixed with a
brew of natural chondrocyte-promoting
compounds and then seeded onto a scaffold that encourages growth and cartilage production. The seeded scaffolding
is later inserted into a cartilage defect in
a patient.
An optimal recipe for the cell-directing
brew is still a mystery, but scientists have
identified several possible ingredients.
Essential to the mix are compounds
called growth factors. The best-studied
is TGF-beta, which is good at jump-start-ing a stem cell to act like a chondrocyte
and produce cartilage, Sandy says. But
TGF-beta can’t work alone; relying too
heavily on TGF-beta, for example, can
steer a stem cell toward making fibrous
tissue, rather than the resilient hyaline
cartilage, he says.
Recent research has focused on
another growth factor called FGF- 2.
Li and Wisconsin colleague Andrew
Handorf reported last year in PLoS
ONE that treating stem cells with FGF- 2
primed them to become hyaline-making
chondrocytes.
FGF- 2 activates a compound called
Sox9 in the stem cell, which in turn
switches on the production of two main
components of cartilage, type 2 colla-
gen and aggrecan, Li says. FGF- 2 might
be best used before cell differentiation,
the point at which a stem cell becomes a
mature cell with a specific role, he says.
Then other growth factors, including
TGF-beta, could push the cartilage-
making process along. A 2010 review
lists a dozen growth factors that affect
stem cells’ ability to differentiate into
chondrocytes.
O
Giving directions
The molecule kartogenin
(shown below) revs up
genes that code for
cartilage proteins, notably
aggrecan, type 2 collagen
and lubricin (right).
SOURCE:
K. JOHNSON ET AL/
SCIENCE 2012
14
Aggrecan
Gene coding for:
Lubricin
Type 2 collagen
Kartogenin (KGN) and stem cell prompting
A protein called vimentin takes a different route to reach the same objective.
To differentiate into a chondrocyte, a
stem cell must take on a round shape,
says Rocky Tuan, a tissue engineer at
the University of Pittsburgh. He and his
colleagues found that vimentin nudges
bone marrow stem cells toward becoming rounded like chondrocytes. Extra
vimentin also boosts genes instrumental
in making type 2 collagen, Tuan’s team
reported in 2010 in the Journal of Cellular Biochemistry.
The blend of compounds required to
create a good hyaline-making chondrocyte may ultimately hinge on the choice
of stem cell itself, Pei says. He proposes
that stem cells derived from the synovial
membrane have an advantage by already
coming from a joint. In fact, synovial
stem cells manufacture a substance, a
type of matrix, that seems particularly
valuable.
Pei’s team mixed the matrix made by
synovial stem cells with FGF- 2 in a low-oxygen environment. That combination,
when added to other synovial stem cells,
enabled those cells to ramp up their
numbers. It also provided them with a
favorable “niche,” a microenvironment
amenable to chondrocyte formation, the
researchers reported last year in Tissue
Engineering, Part A.
Optimizing these conditions improves
the niche and helps the stem cells thrive,
in part because they are free of stress.
Pei’s approach limits reactive oxygen
species, unstable molecules that damage tissues, keeping the stem cells comfortable. Growing outside of niches, Pei
says, “stem cells bear the stresses of the
environment and lose their proliferation
capacity. They become old.”
OH
O
NH
Relative gene expression level
12
10
8
6
4
2
0
KGN
Control 10nM KGN 100nM KGN 1µM KGN 10µM KGN
Kartogenin treatment level (low to high)
A place to reside
Efforts to expand stem cell numbers and
steer them to become chondrocytes go
for naught if the cells can’t hold together
long enough to form a cartilage patch. A
stable home would be a replica of what
scientists call chondrocytes’ extracellular
matrix, the elastic web of cartilage naturally surrounding them in the body.
About a decade ago, Li and Tuan
