Strategy for a Biomimetic Paradigm in Dental and Craniofacial Tissue Engineering - Biomimetics: Advancing Nanobiomaterials and Tissue Engineering - page 130

that BMC do not promote vascular growth by incorporating into vessel
walls but rather by acting as cytokine factories. The injected cells could
not be co-localized with endothelial or smooth muscle cell markers but
strongly accumulated around growing collateral arteries and expressed
several growth factors and cytokines. Indeed, MSC subjected to hypoxia
show increased expression of a panel of genes encoding cytokines related
to arteriogenesis such as VEGF-, MCP-1, bFGF, IL-6, PLGF, etc.
Thus the MSC secretome is a combination of growth factors, cytokines
and chemokines that is further modulated by physiological, pharmacolog-
ical, cytokine or growth factor pre-conditioning and /or genetic manipu-
lation. Taking advantage of the MSC secretome provides an approach to
mimic their effects in vivo in the injury microenvironment. If a cell-free
therapy based on the use of the MSC secretome is to be devised, a clear
understanding of how the lesion microenvironment can affect secretome
profi le is a must [68]. Adult stem cells respond to specifi c cues by their
surroundings thus producing different factors to respond to the dynamic
microenvironment of the lesion [71]. It is also important to note that dif-
ferent progenitor and stem cell sub-populations have different proteomic
profi les and so secrete different factors. It has been established that serum-
deprived MSC are highly angiogenic. They up-regulate the secretion of
prosurvival and angiogenic factors in their conditioned media such as
IGF-1, VEGF-A, angiopoietins, and HGF in addition to IL-6, IL-8, and
CXCL1 [68]. These act both in an autocrine and paracrine fashion [72].
Hypoxia has also been shown to affect angiogenic and osteogenic prop-
erties of MSC. MSC subjected to temporary hypoxia (48 hrs) expressed
more bFGF, VEGF, IL-8, and osteopontin [73] while showing less effective
osteogenic differentiation. This behavior is of utmost clinical relevance
since physiological oxygen tension falls to 1% in the fracture hematoma.
This creates an initial hostile environment for implanted MSC-seeded tis-
sue engineering constructs. MSC appear to react to this environment by
secreting more angiogenic factors and modulating angiogenic processes
to promote vascular invasion of the constructs. The increased secretion of
osteopontin may point to their enhancing macrophage infi ltration which
also interacts with bone formation.
Being a dynamic organ itself, bone is constantly subjected to remod-
eling. Osteoblasts are derived from MSC and during osteogenesis the
secretory profi le of MSC largely changes [74]. It has also been shown that
mouse BMSC implanted in ceramic scaffolds into syngenic mice gave rise
to bone of host origin [75, 76]. It was proposed that the exogenous BMSC
release numerous factors in the immediate implant vicinity thus creating
a likable microenvironment to support recruitment of host cells. This fact
combined with newly formed vascular networks can facilitate the cellu-
lar cross-talk between the implant milieu and the host circulation system
facilitating the recruitment process. Future bone regeneration studies