Biomedical Engineering Reference
In-Depth Information
Stages during Which Morphogens and Cytokines Regulate Mesencyhymal Stem Cell Differentiation
MSC Recruitment (PTHrP, BMP, TNF-
Family)
MSC Commitment (BMP, PTHrP, VEGF)
Proliferative Expansioon
α
Apoptosis
Cell Survival
(BMP, PTHrP, VEGF, Wnts, IGF) (VEGF, FGF, BMPs, IGF)
Enhancement of Differentiated Function
Matrix
Production and
Maturation
(TNF-
α
Family)
Matrix
Mineralization
Collagen X
Fas
Mineral Deposition
CollagenII
PTHrP (R)
Aggrecan (PG)
Collagen IX
APase
BSP
Sox 9
Chondroblast
Mesenchymal
Stem Cell
(MSC)
Differentiation
Committed
Progenitor
Cell
Collagen I
TCF-
b
1
Osteopontin
AlkPhos
BSP
Collagen
Osteocalcin
Mineral deposition
Runx2
Ostrix
Myoblast
Adipoblast
Tendon Fibroblast
Chondroblast
Osteoblast
Osteoblast
Preosteoblast
Mature
Osteoblast
Osteocyte
Figure 2.2.
Schematic summary of the lineage progression of mesenchymal stem-cell (MSC) differentiation. Upper panel: Mul-
tiple stages of the life cycle of an MSC. The morphogenetic regulators of each stage are in parentheses. Lower panel: The separate
stages of each of the major anabolic skeletal cell lineages are indicated with known markers that define each stage of their lineage
progression. PTHrP, parathyroid hormone-related peptide; BMP, bone morphogenetic protein; TNF, tumor necrosis factor; VEGF,
vascular endothelial growth factor; IGF, insulin-like growth factor; FGF, fibroblast growth factor; PG, large proteoglycan; BSP, bone
sialoprotein; TGF, transforming growth factor.
Restoration of the original anatomic geome-
try of the tissue is an important aspect of bone
repair. For this to occur there must be some
relationship between the original structure of
the tissue and the gradients of the morphogens
that promote the developmental process and
the characteristics of the injury. One obvious
f unct iona l role must be at t ributed to t he sig na ls
that initiate and establish the symmetry of
bone repair around the fracture line. These
signals may be thought of as arising from the
marrow or from the injured cortical bone
matrix. In this connection, how the injury
infl uences tissue responses may have consider-
able relevance, because the infl ammatory
signals spread out from the point of origin of
the injury [
]. Data that support the role
infl ammatory cytokines play in the initiation
of skeletal tissue repair come from studies
showing that in the absence of TNF-
16
,
51
,
54
signaling
in receptor-null animals, the callus does not
develop symmetrically around the fracture
line. The absence of TNF-
α
signaling also leads
to a delay in intramembranous and endochon-
dral bone formation. Thus, TNF-
α
signaling
facilitates the repair process, perhaps by stimu-
lating MSC recruitment or differentiation
[
α
68
].
