Page 28 - Human Umbilical Cord Mesenchymal Stem Cells

558 HUANG ET AL.

Table 1. Key Paracrine Factors in Mesenchymal Stem Cell-Based Therapy for Skin Wounds
Paracrine factors Component Main function Ref.
Growth factors ANGPT1 Promoting wound angiogenesis 46,78,100,114,151
bFGF Enhancing wound angiogenesis and granulation tissue 31,65,73,78,93,94,98,99,151
formation
EGF Enhancing wound reepithelialization and granulation 31,46,73,99,111–113,179
tissue formation
HGF Promoting wound angiogenesis, reepithelialization, 31,78,93,94,98–100,112,114,116,119
and granulation tissue formation
IGF-1 Enhancing granulation tissue formation 46,93,94,100,112,179
KGF Enhancing wound reepithelialization 46,49,65,98,100,112,113,117
PDGF Promoting wound angiogenesis and collagen 31,46,49,78,94,98,119,174
metabolism
TGF-b1 Enhancing granulation tissue formation 31,54,57,65,78,93,94,98,99,112,119
VEGF Promoting wound angiogenesis and granulation tissue 31,46,49,54,57,65,68,73,78,93,94,98,
formation 100,101,110–117,119,146,151,174
Immune factors IL-10 Anti-inflammatory cytokine 73,74,174
Antimicrobial LL-37 Inhibiting bacterial growth 84,85,87
peptides Lipocalin Inhibiting bacterial growth 85,86
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Chemokines CCL2 Recruiting inflammatory monocytes and enhancing 68,83,94
wound angiogenesis
31,46,94
SDF-1 Recruiting repair cells, for example, endothelial cells
92,181,182
Evs Exosomes Promoting wound angiogenesis, granulation,
reepithelialization, and collagen remodeling
183,184
MVs Promoting the proliferation, migration and function of
wound repair cells
ANGPT1, angiopoietin-1; bFGF, basic fibroblast growth factor; EGF, epidermal growth factor; EVs, extracellular vesicles; HGF,
hepatocyte growth factor; IGF-1, insulin-like growth factor-1; IL-10, interleukin-10; KGF, keratinocyte growth factor; MVs, microvesicles;
PDGF, platelet-derived growth factor; SDF-1, stromal cell-derived factor-1; TGF-b1, transforming growth factor-b1; VEGF, vascular
endothelial growth factor.

dynamic: when the level of cytokines or chemokines is dele- Reepithelialization
terious to wound healing, MSCs downregulate their expres- Reepithelialization involves new epithelium formation and
sions; conversely, when they are beneficial for wound healing, skin appendage regeneration. 96,97 MSCs participate in the re-
MSCs upregulate their expressions. 82
epithelialization of chronic wounds: they increase the thickness
of new epidermis, facilitate the regeneration of appendage-like
72
structures, and accelerate the speed of reepithelialization.
Antimicrobial activities
Besides epithelial cell differentiation, MSCs secrete a great
The antimicrobial function of MSCs is mediated by two deal of paracrine factors (e.g., epidermal growth factor) to
mechanisms: (i) enhancing the ability of immune cells to improve the survival, proliferation, migration, and differentia-
kill bacteria 83–85 and (ii) secreting antimicrobial peptides, tion of cells involved in wound reepithelialization. 46,98–100
such as LL-37, to kill bacteria directly. 83,85–87 These
mechanisms reduce excess inflammation and are helpful to
prevent wound infection. 88 Animal Studies
A large number of animal studies have been performed to
determine the therapeutic potential of MSCs for different
Angiogenesis 101–104
skin wounds, including acute skin wounds, thermal
In normal wound healing, the concentration of angiogenic burns, 105–107 diabetic wounds, 49,108–112 radiation burns, 113–118
growth factors increases after injury, reaching a peak slightly and pressure sores. 119–121 Notably, big variations exist in these
before maximum capillary formation and decreasing gradually studies, such as cell source, animal model, and cell delivery
to nearly undetectable levels. 89 In chronic wounds, the an- method. Interestingly, in most studies, the outcomes are quite
giogenic growth factors are confronted with antiangiogenic similar: MSCs promoted not only the healing of acute wounds
conditions (e.g., increased levels of matrix metalloprotei- and thermal burns 101–107 but also the healing of chronic
nases), 90,91 which lead to insufficient wound angiogenesis. wounds (Fig. 1), typically with an accelerated wound closure
MSCs enhance angiogenesis in chronic wounds, mainly and improved healing quality (Table 2).
through two actions: (i) direct differentiation into endothelial Regarding the seed cells, different sources of MSCs have
cells and (ii) the secretion of various bioactive factors, in- been explored in animal studies, such as cells derived from
cluding exosomes, 92 growth factors, 93,94 and chemokines, 94 bone marrow, 108,110,111 adipose tissue, 112 and umbilical
which facilitate new blood vessel formation by stimulating the cord. 49,109 Since most of current knowledge of MSC biology
recruitment and proliferation of host endothelial cells. 46,94,95 is based on the research of cells derived from bone marrow,