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MSCS FOR CHRONIC WOUND TREATMENTS 557

CD40, and CD86) and, thus, lack significant immunogenici- have been observed at the skin wound sites, 54,55 and notably,
ty 36,37 ; (ii) they regulate the inflammation of injured or dis- they secreted bioactive factors to recruit other repair cells
eased tissues toward tissue regeneration 38,39 ; (iii) they produce from the host animals. 56–58 A plethora of chemokines, growth
a variety of bioactive factors to support the normal function of factors, and receptors was involved in the recruitment of
resident cells in hostile microenvironments. 40–42 MSCs. 59–62
A great deal of inherent similarities have been identified
among MSCs isolated from different tissue origins, such as Cell differentiation
core cell markers, conserved expression of genes, cytokines,
and growth factors; however, there are subtle differences As observed in the fate tracing of transplanted MSCs, a
that should be taken into consideration when developing small portion of cells can differentiate into skin cells at the
7,63–72
MSC-based therapy. 43,44 For instance, the proliferation and wound sites. For instance, in a mouse excisional skin
differentiation of MSCs varied obviously among different wound model, Wu et al. reported that topically adminis-
tissues. 45 trated MSCs differentiated into keratinocytes and formed
63
glandular structures at the wound bed. In other studies,
MSCs were found to differentiate into endothelial cells 8,68–71
The Critical Roles of MSCs in Wound Healing 7,72
and skin appendages. After allogenic bone marrow re-
The mechanisms of MSC-based wound therapy have not constitution, donor-derived BM-MSCs have been observed to
been fully delineated, yet, two mechanisms are generally participate in the hair regeneration of host mice. 7
postulated: (i) direct differentiation into skin cells and (ii)
the secretion of trophic factors (Fig. 1). Considering the Immunomodulation
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poor engraftment of MSCs at chronic wounds, it is widely
believed that the therapeutic effects depend predominantly In chronic wounds, high levels of inflammatory factors
on their paracrine actions by which MSCs secret a multitude prevent wound healing. Due to their immunomodulation
of soluble factors (Table 1), such as growth factors, immune activities, MSCs are helpful in overcoming the hyperin-
factors, chemokines, and exosomes, to enhance the survival, flammation of chronic wounds, which promotes the transi-
recruitment, and function of wound repair cells. This finding tion of wound healing from the inflammatory phase to the
is supported by a growing body of evidence: for instance, proliferative phase. MSCs not only coordinate the actions of
73,74
MSC-conditioned medium has a potent healing effect on inflammatory cells but also inhibit the deleterious ef-
74–76
skin wounds. 46–49 fects of inflammatory cytokines.
When activated by inflammatory factors, MSCs become
potently immunosuppressive, secreting soluble mediators (e.g.,
Cell recruitment
NO and prostaglandin E2) to decrease excessive immune re-
76–78
MSCs can home to injured skin and participate in wound actions. They suppress T cell proliferation, B lymphocyte
healing. In the mouse chimeric bone marrow transplantation differentiation, and natural killer cell functions; also, they
model, several groups reported the migration of bone marrow modulate macrophage phenotypes, disturb dendritic cell func-
cells into skin wounds. 50–53 Likewise, after systemic admin- tions, 78–81 and decrease the secretionofproinflammatory cy-
istration, exogenous bone marrow-derived MSCs (BM-MSCs) tokines. 73,74,76 Notably, the immunomodulation of MSCs is

FIG. 1. Transplantation of MSCs enhance chronic wound healing through multiple repair mechanisms. bFGF, basic
fibroblast growth factor; EGF, epidermal growth factor; IL-10, interleukin-10; MSCs, mesenchymal stem cells; SDF-1,
stromal cell-derived factor-1; TGF-b1, transforming growth factor-b1; VEGF, vascular endothelial growth factor. Color
images are available online.