Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 732

Angiogenesis appears to eliminate hypoxic environment mainly from capil-
lary sprouts and endothelial cell migration, accessorily via bone marrow-derived
endothelial progenitor cells, owing primarily to vascular endothelial VEGFa and
fibroblast FGF2 growth factors.
Cell migration and signal release lead to tissue reconstruction. Tissue remodeling
is characterized by a balance among synthesis, deposition, and degradation. The
connective tissue is able to receive water (edema), minerals, molecules, and cells.
The edema region is invaded by various substances and cells to become an
inflammatory granuloma. Granulation tissue is formed, composed of a matrix of
fibrin, fibronectin, glycosaminoglycans with proliferating endothelial cells, and
fibroblasts mixed with macrophages and lymphocytes. Epithelialization occurs early
in wound repair.
Angiogenesis stimulated by TNF leads to formation of new capillaries that

deliver nutrients to the healing region. Fibroblasts differentiate. Wound extracellular
matrix, composed of collagen and elastin fibrils interspersed with glycosaminogly-
cans, polysaccharides, and proteoglycans, fulfills a structural and regulatory role in
cell behavior by contact or as a reservoir of growth factors. Fibroblasts transform
into myofibroblasts with contractile features.
During the final maturational phase, the tissue contracts. Collagen turnover is
increased. Remodeling of the collagen fibers with degradation by matrix met-
allopeptidase manufactured by macrophages and fibroblasts among others, and
with synthesis stimulated by cytokines, such as TNF

α

α and IL1, is associated with

reorientation of collagen fibers.
Tissue injury creates an environment that releases growth factors and neurohor-
mones to recruit stromal-like cells for the repair process. In response to cytokines,
stromal-like cells can migrate with hematopoietic stem cells and endothelial
precursor cells and then differentiate.
Neuropeptide substance-P is able to induce migration of human mesenchymal
stem cells from the bone marrow stroma, to increase expression of several matrix
metallopeptidases for cell mobilization, and to stimulate proliferation of bone
marrow stromal mesenchymal stem cells via extracellular signal-related kinases
ERK1 and ERK2. Substance-P also primes translocation of

β -catenin to the nucleus,

so that the TCF/LEF- Ctn pathway involved in stem cell self-renewal may help to

repopulate the bone marrow stroma. CD29

β

β 1 -integrin) stromal-like stem cells
are able to circulate in the blood stream owing to, at least partly, substance-P [ 1475 ].

+ (

11.6.5 Modeling of Healing

Simple models of wound healing are based on conservation equations based on
cell and matrix density and concentration of stimulators and inhibitors in cell
division [ 1476 ]. The simplest model consists of 2 conservation equations in the case