Page 29 - Human Umbilical Cord Mesenchymal Stem Cells

MSCS FOR CHRONIC WOUND TREATMENTS 559

Table 2. Animal Studies of Mesenchymal Stem Cell-Based Therapy for Chronic Wounds
Wound Animal Source Delivery Outcome Ref.
Diabetic Mouse BM Local injection Enhanced reepithelialization, granulation, and 108
wounds vascularization
Mouse UC Subcutaneous injection Improved angiogenesis and accelerated wound 49
closure
Rat UC Intraarterial injection Reduced ulceration area and promoted 109
epithelialization
Rat BM Intramuscular injection Promoted angiogenesis and granulation tissue 110
formation
Rat BM Subcutaneous injection Reduced inflammation and enhanced wound 111
healing
Rat AT Local transplantation of cell Accelerated wound healing and vascularization 112
sheet with artificial skin
Radiation Mouse BM Intradermal injection Reduced irradiation-induced inflammation 113
burns Mouse UCB Local transplantation with Enhanced wound healing and angiogenesis 114
hydrogel
Mouse UCB Local implantation with PRP Increased wound closure rate and angiogenesis 116
Rat UC Subcutaneous injection Promoted neovascularization and 115
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reepithelization
Rat BM Local injection with BMP-2 Accelerated wound healing and enhanced 117
angiogenesis
118
Minipig AT Intradermal injection at the Skin healing without necrosis or uncontrollable
wound site pain
Pressure Mouse AT Subcutaneous injection at the Accelerated wound closure, improved 119
sores wound epidermal/dermal architecture, increased
adipogenesis, reduced inflammation
Mouse BM Intradermal injection at the Suppressed the development of pressure ulcers 120
wound after cutaneous ischemia-reperfusion injury
Foal AF Local implantation with PRP Accelerated wound healing, without any side 121
effect
AT, adipose tissue; AF, amniotic fluid; BM, bone marrow; PRP, platelet-rich plasma; UC, umbilical cord; UCB, umbilical cord blood.

BM-MSCs are widely regarded as the main cell source for Furthermore, the innate and acquired immune systems of
future clinical applications 122 ; therefore, the wound healing rodents and humans are quite different at the cellular, tissue,
potential of BM-MSCs has been the focus of many animal and systemic levels, 132–134 such as the percentages of pe-
studies. ripheral blood leukocytes in humans and mice. 135 In addi-
Based on the inherent ability of MSCs to migrate into injured tion, the number and type of cell infiltrate and response in
123–125
skin, systemic cell delivery methods have been used in wound healing are not the same in rodents and hu-
74,102,107,126 132,134,136–138
animal studies, including intravenous infusion, in- mans. Since these species variations greatly
traarterial injection, 109 and intraperitoneal transplantation. 101 In impact wound healing outcomes and timelines, 136,138,139
some of these studies, MSCs were found to differentiate into they should be taken into consideration when choosing an
skin cells at the wound sites. 8,126 The transplantation of MSCs animal model and interpreting the results of animal studies.
increased the levels of prohealing factors at the wounds, 74,101 Given this, reproducible animal models that closely mi-
and improved the strength of repair tissues. 127 mic human wound healing are highly encouraged in the
Although systemic cell delivery methods are easy to operate, future, such as porcine skin wound models. 118,140 However,
it should be noted that the efficiency of cell engraftment at the until now, none of existing animal models can successfully
wounds is low. 54,128 Consequently, alternative methods have recapitulate the heterogeneity and complexity of chronic
been used to improve cell retention at the wounds, such as local wounds in humans. 141,142 It is noteworthy that the animal
injection of cell suspension 103–105,108,110,111 or scaffold-assisted models in Table 2 are not really true chronic wound models,
cell grafting. 129,130 By these means, the transplantation of but are more delayed wound models.
MSCs also resulted in improved wound healing, showing de-
creased inflammation, 111 increased angiogenesis, 49,106,110 im- Clinical Trials
proved granulation, 102,108,110 and accelerated closure. 49,108,111
Because of the low cost of the animals and their rela- Since MSC-based therapy has shown improved wound
tively easy availability, rodent models have been widely healing in many animal studies, the use of MSCs for chronic
used in the study of MSC-based wound healing. However, wounds continue to advance toward clinical trials. On the
there are considerable differences between the healing public website of the Clinical Trials Data Bank at the Na-
mechanism of human wounds and rodent wounds. In rodents, tional Institutes of Health (www.clinicaltrials.gov), 38
skin wounds heal mainly by wound contraction, whereas clinical trials were registered to investigate the healing po-
human skin wounds heal primarily by reepithelialization and tential of MSCs for chronic wounds (as at December 30,
granulation. 131 2019) (Table 3), mainly lower extremity ulcers and pressure