Page 34 - Human Umbilical Cord Mesenchymal Stem Cells

564 HUANG ET AL.

transformation of cells, the risk of promoting tumor growth The carrier used to deliver MSCs markedly influences
in vivo, and the potential of cell maldifferentiation. their paracrine activities and differentiation potential. 170–172
During ex vivo expansion, it has been reported that ge- Safe and efficient cell delivery methods are encouraged
nomic instability accumulated in the latter passages of in the future. For chronic wounds, scaffold-assisted cell
MSCs, 160,161 causing the concern about the potential ma- grafting has shown promising outcomes in many preclinical
lignant transformation of graft cells. Therefore, when de- studies, 114,116,128,129,173,174 which may be the way forward
veloping clinical trials, the suitable cell passages should be for clinical translation. For instance, delivering MSCs
determined; especially, the genotype of graft cells should be within a fibrin gel has been reported in several clinical tri-
analyzed before cell transplantation. als. 145,156 Apart from fibrin gel, platelet-rich plasma (PRP)
In some animal models, it has been observed that MSCs has been recognized as a promising cell delivery vehicle for
can home to tumor sites and favor tumor growth and pro- chronic wound healing. 121,175 PRP contains fibrin and high
gression. 162,163 Although current clinical trials, to the best of concentrations of growth factors. It has been reported that
our knowledge, do not report any adverse cases of tumor PRP can restart the healing process of chronic wounds that
176
formation after the administration of MSCs in vivo, it is still were recalcitrant to other treatments. Interestingly, when
necessary to rule out any negative effects by strict cell- in combination with MSCs, PRP improves the therapeutic
quality control and long-term follow-up. Furthermore, the efficacy of MSCs by enhancing their survival, proliferation,
possibility of maldifferentiation of graft cells, another se- and the secretion of angiogenic factors. 58,116,177 Based on
vere side effect, should be avoided in MSC-based therapy. these encouraging studies, the clinical application potential
For example, in a rat acute glomerulonephritis model, MSCs of MSC-laden PRP deserves further investigation.
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have been observed to maldifferentiate into adipocytes,
which resulted in chronic kidney disease. 164
It is generally acknowledged that the paracrine action of Future clinical trials
MSCs is the primary wound healing mechanism of MSC- Despite the promising results achieved in animal studies
based therapy. Since MSC conditioned medium contains and clinical trials, there is no sufficient evidence to support
various kinds of paracrine factors secreted by MSCs during the utilization of MSCs as a standard therapy for chronic
in vitro culture, it is considered as a promising strategy to wounds. First, the number of patients recruited in current
aid chronic wound healing, which is verified by several clinical trials, both complete and ongoing, is small.
animal studies. 42,46–49,67,94 Importantly, comparing with Second, most clinical studies lack an appropriate control,
direct transplantation of MSCs in vivo, MSC-conditioned which raises some concerns about whether MSC-based
medium avoids the risk of maldifferentiation or malignant therapy is superior to conventional wound treatments. It is
transformation of grafted cells, thus providing a much safer reasonable to use standard wound care as the control group
approach. Despite this, more preclinical and clinical studies, to determine the safety and efficiency of MSC-based ther-
especially clinical evaluation of the safety and efficiency of apy. Notably, various conventional cell-based therapies,
MSC-conditioned medium, are required in the future. especially bioengineered skin substitutes composed of fi-
broblasts and keratinocytes, have been approved by the U.S.
FDA and commercialized for the treatment of chronic ul-
Cell treatment methods 178
cers. Although it has been demonstrated in animal studies
To maximize the healing potential of MSCs, particular that fibroblast transplantation was less effective than MSC-
attention should be devoted to optimize the dose, time, based therapy for chronic wounds, 179,180 no clinical study
frequency, and route of treatment. The effective dose of has been conducted to determine whether MSC-based
MSCs has not been clearly defined according to different therapy was superior to conventional cell-based therapy.
clinical indications of chronic wounds. Although one-time Definitely, a direct comparison among these approaches in
administration is acceptable for many acute injuries, re- well-designed clinical studies will provide valuable infor-
peated administration of MSCs at certain intervals has been mation for the wound care providers to make a suitable
reported to greatly influence the healing outcomes of wound treatment decision. Therefore, in future clinical
chronic diseases, such as chronic kidney disease and liver studies, it is helpful to use conventional cell-based therapy
fibrosis. 165,166 Thus, for chronic wounds, the treatment fre- as the positive control to determine the efficiency of MSC-
quency needs to be better defined on the basis of wound based therapy.
types. Third, there are many variations in the clinical trials (e.g.,
In addition, the treatment time frame influences the effi- cell source, dose, wound type), which hinder a direct com-
ciency of MSC-based therapy. Generally, tissue healing parison among different studies. Furthermore, some incon-
includes three phases: the injury phase (hours), the repair sistency was noted in the inclusion/exclusion criteria of
phase (days), and the remodeling phase (weeks). The opti- patients among different studies. It is important to establish
mal time to administrate MSCs depends on the condition of suitable and consistent criteria for patient selection, which
diseases, such as the severity of tissue injury. In the treat- lay the foundation for further comparison of different
ment of myocardial infarction, it is believed that the repair treatments. Since few randomized, controlled clinical trials
phase (i.e., 4–7 days after infarction) is the optimal time have been conducted thus far, high-quality clinical studies
frame for stem cell transplantation, 167,168 while in the are badly required in the future, especially large-scale,
treatment of traumatic brain injury, MSCs should be grafted randomized, double-blind, controlled clinical trials with
as soon as possible. 169 To date, the optimal therapeutic time long-term follow-up.
frame of MSCs remains a puzzle in chronic wound healing To achieve a better comparison among different studies
and needs further investigation. and to build a robust pool of clinical evidence, standardized