Page 26 - Human Umbilical Cord Mesenchymal Stem Cells

556 HUANG ET AL.

wounds impose a heavy financial burden on the health care ate and migrate into the wound bed to form new blood ves-
system. For instance, the treatment of chronic wounds costs sels, which enhance granulation and reepithelialization.
more than $25 billion annually in the United States. 1 The remodeling phase begins from 2 to 3 weeks post-
To help chronic wounds heal naturally, conventional injury and may last for 1–2 years or even longer. 11 During
wound management utilizes diverse strategies to control the this phase, randomly deposited granulation tissue remodels
underlying causes (infection, ischemia, and so on). Besides into an organized structure. The tissue tensile strength in-
traditional wound treatments (physical debridement, topical creases gradually, achieving 70–80% of normal skin after 3–4
12
antibiotics, compression bandages, and so on), advanced months. Meanwhile, the cellularity and vascularity decrease
wound therapies using tissue-engineered skin grafts or gradually, resulting in a relatively acellular mass of epithe-
2
growth factors attract considerable interest. However, de- lialized extracellular matrix.
spite some progress achieved, the clinical outcome remains
unsatisfactory: more than 50% of chronic wounds are re- Chronic Wounds
3
fractory to current therapies, highlighting an urgent need
Any impairment in the process of normal wound healing
for effective treatments. 13
leads to chronic wounds or hypertrophic scars. Chronic
Mesenchymal stem cells (MSCs) have been regarded as a
wounds are usually defined as wounds that fail to heal
promising therapeutic option for many injured tissues or
diseases without effective treatments. 4 The presence of within 3 months, typically showing a continuous inflam-
MSCs in skin tissues, 5,6 coupled with their integral roles in matory state with an increased presence of neutrophils as the
14–16
normal wound healing and skin homeostasis, 7,8 implies that typical biological marker. Most chronic wounds can be
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MSCs may be beneficial for chronic wound healing. Thus, a categorized into arterial, venous or diabetic ulcers, and
17,18
great number of animal studies have been carried out to pressure sores. They persist as a significant health care
explore the therapeutic potential of MSCs and their secre- problem, particularly with increasing number of patients and
tions (conditioned medium, extracellular vesicles, exosomes, the lack of efficient treatments.
Although there are many differences among the etiology
and so on) for difficult-to-treat wounds. With increasing and symptomatology of different chronic wounds, the un-
understanding of the repair mechanisms, MSC-based therapy derstanding of the cellular and molecular mechanisms
has progressed from animal studies to clinical trials. causing the wounds difficult-to-heal has increased greatly in
Based on current data in the literature, we review, in this the past few decades (for detailed reviews, refer to Refs. 17–22 ).
article, the preclinical studies and clinical trials using MSCs Generally, the microenvironment of chronic wounds is
to treat different types of chronic wounds, including lower distinct from normal wounds, characterized by impaired
extremity ulcers, pressure sores, and radiation burns. After angiogenesis, increased infection, and, particularly, pro-
introducing the biology of MSCs, normal wound healing, longed inflammation that promotes the degradation of pro-
and chronic wounds, we detail the crucial roles of MSCs in healing factors. 18,23 Furthermore, compared to normal
skin wound healing. Animal studies to determine the fea- wounds, the cells resident in chronic wounds, such as fi-
sibility and efficiency of MSCs are outlined, followed by a 24 22
broblasts in venous ulcers, diabetic ulcers, and pressure
focus on clinical studies about the applications of MSCs in 25
scores, are more senescent and less sensitive to growth
chronic-wound treatment. Finally, we discuss major chal-
factors. All these unfavorable properties make chronic
lenges that need to be addressed before the widespread
wounds extremely hard to heal.
clinical application of MSCs for chronic wound healing.
Mesenchymal Stem Cell Biology
Normal Wound Healing
MSCs are a heterogeneous group of adult stem cells
As a complex process to restore skin integrity after injury, arising from the embryonic connective tissue. They have
normal wound healing involves sophisticated interplays been successfully isolated from a variety of human tissues
among cells, the extracellular matrix, and soluble molecules. (bone marrow, fat, synovium, cartilage, skin, placenta, and
It typically comprises three overlapping phases: inflamma- so on). 26 They are plastic-adherent cells with self-renewal
tion, proliferation, and remodeling. ability and, under specific conditions, can differentiate into
In the inflammation phase, the disruption of blood vessels osteoblasts, adipocytes, and chondrocytes. They share some
activates the coagulation cascade, which leads to the formation features with pericytes in vitro, 27 but the in vivo identity is
of a fibrin clot at the wound bed. As the first cell type arriving poorly understood. 28 Despite years of research, no MSCs-
at the wound bed, neutrophils clear microbes, dead cells, and specific marker has been identified; thus, the International
9
wound debris. They secrete a myriad of cytokines and growth Society for Cellular Therapies has proposed a set of minimal
factors to attract additional neutrophils and other cells. Five to criteria to define human MSCs. 29
7 days after injury, macrophages at the wound adopt an anti- As a reservoir of endogenous cells for tissue repair and
inflammatory role, secreting various growth factors to facilitate regeneration, MSCs actively respond to biological signals
granulation, angiogenesis, and reepithelialization. 10 Notably, associated with inflammation, necrosis, and tissue injury. 30
excessive inflammation inhibits normal wound healing. They have been found to differentiate into the cells of dam-
The proliferation phase starts around the fourth day after aged tissues in many animal models, such as diabetic skin
33
11
injury and may last for about 2 weeks. Much happens in this ulcers, 31 osteoarthritis, 32 and corneal damage ; furthermore,
phase, including fibroplasia, angiogenesis, granulation, and they can migrate into distant injured tissues to facilitate tissue
reepithelialization. Fibroblasts initiate granulation, bringing repair. 34,35 For stem cell-based therapy, MSCs possess many
wound edges closer together by differentiating into contractile attractive properties: (i) they do not express major histocom-
myofibroblasts. Endothelial cells around the wound prolifer- patibility complex class II or costimulatory molecules (CD80,